Compound, compositions, and methods

ABSTRACT

Compounds having activity as LRRK2 inhibitors are disclosed. The compounds are of formula (I) including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) to U.S.Provisional Application Ser. Nos. 62/258,244, filed Nov. 20, 2015,62/259,165, filed Nov. 24, 2015, 62/307,285, filed Mar. 11, 2016,62/310,632, filed Mar. 18, 2016, 62/350,927, filed Jun. 16, 2016,62/350,988, filed Jun. 16, 2016, 62/351,004, filed Jun. 16, 2016,62/351,083, filed Jun. 16, 2016, 62/411,011, filed Oct. 21, 2016,62/411,064, filed Oct. 21, 2016, and, where the contents of each isincorporated herein by reference in its entirety.

FIELD

The present disclosure relates generally to novel pyrazole-substitutedpyrimidines and their use as therapeutic agents, for example, asinhibitors of LRRK2.

BACKGROUND

Neurodegenerative diseases such as Parkinson's disease, amyotrophiclateral sclerosis (ALS), Alzheimer's disease, Lewy body dementia, andHuntington's disease affects millions of people. Parkinson's disease isa chronic, progressive motor system disorder characterized by selectivedegeneration and cell death of dopaminergic neurons in the substantialnigra region of the brain. This leaves patients with impaired ability todirect and control their movements. The cause of the disease wasgenerally considered to be sporatic and unknown, but significantadvancements in understanding have been made in the last 15 years.

The genetic basis for the disease and associated pathogenic mechanismshave led exploration of the gene encoding leucine-rich repeat kinase 2(LRRK2) protein and its association with hereditary Parkinson's disease(Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, 601-607). LRRK2 is amember of the ROCO protein family and shares 5 conserved domains withall other family members. Many mis-sense mutations to the LRRK2 genehave been linked with autosomal dominant Parkinson's disease in familialstudies Trinh and Farrar, Nature Reviews in Neurology. Vol. 9, 2013,445-454; Paisan-Ruiz et al., J. Parkinson's Disease, Vol. 3, 2013,85-103). The most common pathogenic mutation, G2019S, occurs in thehighly conserved kinase domain of LRRK2 (See Gilks et al., Lancet, Vol365, 2005, 415-416). In vitro studies indicate Parkinson'sdisease-associated mutation leads to increased LRRK2 activity and adecreased rate of GTP hydrolysis (Guo et al., Experimental CellResearch, Vol. 313(16), 2007, 3658-3670). This evidence suggests thekinase and GTPase activities of LRRK2 are important for pathogenesis andthe LRRK2 kinase domain may regulate overall LRRK2 function (SeeCookson, Nat. Rev. Neurosci., Vol. 11, 2010, 791-797).

While progress has been made in this field, there remains a need forimproved inhibitors of the LRRK2 receptor which are useful for treatmentof various neurodegenerative diseases, such as Parkinson's disease,Alzheimer's disease and amyotrophic lateral sclerosis.

SUMMARY

Provided herein are compounds that are useful as inhibitors of LRRK2.The disclosure also provides compositions, including pharmaceuticalcompositions, kits that include the compounds, and methods of using (oradministering) and making the compounds. The disclosure further providescompounds or compositions thereof for use in a method of treating adisease, disorder, or condition that is mediated, at least in part, byLRRK2. Moreover, the disclosure provides uses of the compounds orcompositions thereof in the manufacture of a medicament for thetreatment of a disease, disorder, or condition that is mediated, atleast in part, by LRRK2.

In one embodiment, provided is a compound of formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or a mixture ofstereoisomers, tautomer or prodrug thereof, wherein:

Z is N or CH;

R¹ is halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkyloxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,aminocarbonyl, or heterocyclylcarbonyl, wherein each is optionallysubstituted; and R⁵ is H; or

R¹ and R⁵ together with the atom to which they are attached form a5-membered ring having the structure:

Y is N or CR⁶;

R⁶ is H, halo, cyano, C₁-C₆ alkyl. C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,—S(O)_(w)(C₁-C₆ alkyl), cycloalkyl, heterocyclyl, heteroaryl, aryl,acyl, or amido, wherein each is optionally substituted;

R¹⁰ is H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or cycloalkyl;

R² is C₁-C₆ alkyl, cycloalkyl, cycloalkylalkyl, C₁-C₆ alkoxy,cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,heterocyclylalkyloxy, amino, C₁-C₆ alkylamino, cycloalkylamino,cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino,wherein each is optionally substituted;

R^(3a) and R^(3b) are each independently H, halo, cyano, amino, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ heteroalkyl, C₁-C₆ cyanoalkyl,C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylsulfonylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aminocarbonyl,heterocyclylcarbonyl, or -L²-R⁸, wherein each is optionally substituted;

or R⁴ and either R^(3a) or R^(3b) when attached to an adjacent carbon,together with the atoms bound thereto join to form a heterocyclyl orheteroaryl, wherein each heterocyclyl or heteroaryl is optionallysubstituted;

or R^(3a) and R^(3b) when attached to an adjacent carbon, together withthe atoms bound thereto join to form a cycloalkyl, heterocyclyl, orheteroaryl, wherein each cycloalkyl, heterocyclyl, or heteroaryl isoptionally substituted;

R⁴ is H, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆haloalkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl,C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl, heterocyclylcarbonyl, or -L¹-R⁷, wherein each isoptionally substituted;

L¹ is —S(O)_(p)—, —S(O)_(p)N(R⁹)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—, or—C(O)N(R⁹)—;

each L² is independently —O—, —S(O)_(m)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—,—OC(O)—, —C(O)N(R⁹)—, —N(R⁹)C(O)—, —N(R⁹)C(O)—, —OC(O)N(R⁹)—,—N(R⁹)C(O)N(R⁹)—, —S(O)_(p)N(R⁹)—, —N(R⁹)S(O)_(p)N(R⁹)—, or—N(R⁹)S(O)_(p)—;

R⁷ is C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,wherein each is optionally substituted;

each R⁸ is independently C₁-C₆ alkyl. C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl, wherein each is optionallysubstituted;

each R⁹ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂₋₆alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl;

each p is independently 1 or 2;

each w is independently 0, 1, or 2; and

each m is independently 0, 1, 2, or 3;

provided that:

a) when R⁵ is H, then Z is N, and R² is C-heterocyclyl, which isoptionally substituted; andb) when R¹ and R⁵ together with the atom to which they are attached formthe 5-membered ring, then either:

i) R² is C₁-C₆ alkoxy, cycloalkyloxy, cycloalkylalkyloxy,heterocyclyloxy, heterocyclylalkyloxy, amino, C₁-C₆ alkylamino,cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, orheterocyclylalkylamino; Z is N; R⁵ is H; Y is N or CR⁶; and R⁶ is halo,C₁-C₆ haloalkyl or cycloalkyl; or

ii) R² is C₁-C₆ alkyl, cycloalkyl or cycloalkylalkyl, wherein each isoptionally substituted.

In one aspect, provided is a compound of formula (II):

or a pharmaceutically acceptable salt, prodrug, stereoisomer, or amixture of stereoisomers thereof, wherein:

R⁴¹ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R⁴⁵:

R⁴² is:

-   -   a fused bicyclic ring system having a heterocyclyl or cycloalkyl        fused to a heteroaryl, wherein the ring system is attached to        the remainder of the molecule via the heterocyclyl or cycloalkyl        and the ring system is independently optionally substituted with        one or more halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, amino, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆        cyanoalkyl, C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆        alkylene-S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —C₁₋₆        alkylene-C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C₁₋₆ alkylene-SO₂NR⁴⁶R⁴⁷, —C₁₋₆        alkylene-NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)R⁴⁶, —C₁₋₆        alkylene-C(O)R⁴⁶, —C₁₋₆ alkylene-OC(O)R⁴⁶, —C₁₋₆        alkylene-C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, —C₁₋₆        alkylene-O—C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)OR⁴⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ alkoxyalkyl substituted with one or more substituents        independently selected from halo, amino, cyano, hydroxy, C₁₋₆        haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆        alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷,        —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        aryl, arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ haloalkyl substituted with one or more substituents        independently selected from amino, cyano, hydroxy, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl,        —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,        —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   C₁₋₆ cyanoalkyl optionally substituted with one or more        substituents independently selected from halo, amino, hydroxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, —S(O)₂(C₁₋₆ alkyl),        —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶,        —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶(O)OR⁴⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₃₋₁₀ cycloalkyl substituted with one or more substituents        independently selected from amino, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆        alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆        hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted with one or more        halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl, wherein the        heterocyclyl, heteroaryl, or heteroarylalkyl are optionally        substituted with one or more substituents independently selected        from C₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo; or    -   —X—C(R⁴⁸)(R⁴⁹)(R⁵⁰), wherein:        -   X is C₁₋₆ alkylene optionally substituted with one or more            halo;        -   R⁴⁸ and R⁴⁹, together with the carbon atom to which they are            attached, form an optionally substituted C₃₋₁₀ cycloalkyl;            and        -   R⁵⁰ is cyanoalkyl, C₁₋₆ alkoxyalkyl, C₂₋₆alkenyl, C₂₋₆            alkynyl, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆            hydroxyalkyl, C₁₋₆ alkoxyalkyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,            heteroaryl, or heteroarylalkyl;

R^(43a) and R^(43b) are each independently H, halo, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl,C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl),cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, amido, or —C(O)R⁴⁵;

R⁴⁴ is cycloalkyl, C-heterocyclyl, —N(R⁵¹)₂, —OR⁵¹, or —SR⁵¹;

each R⁴⁵ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R⁵²)₂, orheterocyclyl, wherein each C₁₋₆ alkyl, C₁₋₆ alkoxy, or heterocyclyl isoptionally substituted;

each R⁴⁶ and R⁴⁷ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl,wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionallysubstituted;

each R⁵¹ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl,—C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₃₋₆ cycloalkyl optionally substitutedwith one or more C₁₋₆ alkyl, C₃₋₆ cycloalkylalkyl optionally substitutedwith one or more C₁₋₆ alkyl, heterocyclyl optionally substituted withone or more R⁵³, or heterocyclylalkyl optionally substituted with one ormore R⁵³; or

two R⁵¹, together with the nitrogen to which they are attached, form athree- to six-membered heterocyclyl optionally substituted with one ormore R⁵³;

each R⁵² is independently H or optionally substituted C₁₋₆ alkyl;

each R⁵³ is independently C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, oxo, C₁₋₆alkoxy, amino, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ alkoxyalkyl, cyano,heterocyclyl, heterocyclylalkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylalkyl,C₃₋₆ cycloalkylsulfonyl, —C(O)R⁵⁴, or —C₁₋₆ alkylene-C(O)R⁵⁴;

each R⁵⁴ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, amino optionallysubstituted with halo, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxy, C₁₋₆alkoxyalkyl, C₁₋₆ cyanoalkyl, —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆aminoalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl, heterocyclyl, orheterocyclylalkyl; and

provided that when R⁴⁴ is cycloalkyl, —N(R⁵¹)₂, or —OR⁵¹, then R⁴² isnot an unsubstituted C₁₋₆ cyanoalkyl.

In another embodiment, a pharmaceutical composition is providedcomprising a compound as described herein (e.g., a compound of FormulaI, II, A-I, B-I, C-I, or D-I, or any subformula thereof), or astereoisomer, mixture of stereoisomers, pharmaceutically acceptablesalt, tautomer, or prodrug thereof, and a pharmaceutically acceptablecarrier, diluent or excipient.

In another embodiment, a method for treating a disease or conditionmediated, at least in part, by LRRK2, in a subject in need thereof isprovided, the method comprising administering to the subject aneffective amount of the pharmaceutical composition comprising a compoundas described herein (e.g., a compound of Formula I, II, A-I, B-I, C-I,or D-I, or any subformula thereof), or a stereoisomer, mixture ofstereoisomers, pharmaceutically acceptable salt, tautomer, or prodrugthereof, and a pharmaceutically acceptable carrier, diluent, orexcipient.

In some embodiments, the method is for treatment of a neurodegenerativedisease, a cancer, an inflammatory disease. In some embodiments, themethod is for enhancing cognitive memory.

In another embodiment, a compound of Formula I, II, A-I, B-I, C-I, orD-I, or any subformula thereof, is provided for use in therapy. In someembodiments, the compound is provided for use in the treatment of aneurodegenerative disease, cancer, or an inflammatory disease.

In another embodiment, provided is a method for preparing a compound offormula (I), comprising coupling a compound of formula (b):

wherein X is halogen, with a compound of formula (c):

under conditions to provide the compound of formula (I),

wherein R¹, R², R^(3a), R^(3b), R⁴, R⁵, and Z are as defined herein.

In another embodiment, provided is a method for preparing a compound offormula (II), comprising coupling a compound of formula (II-a):

wherein X is a leaving group (e.g., halo), with a compound of formula(II-b):

under conditions to provide the compound of formula (II),

wherein R⁴¹, R⁴², R^(43a), R^(43b), and R⁴⁴ are as defined herein.

These and other aspects of the disclosure will be apparent uponreference to the following detailed description.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of thedisclosure. However, one skilled in the art will understand that theinvention may be practiced without these details.

1. Definitions

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is, as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present disclosure. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this disclosure belongs.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line or a dashed line drawn through a line in astructure indicates a specified point of attachment of a group. Unlesschemically or structurally required, no directionality orstereochemistry is indicated or implied by the order in which a chemicalgroup is written or named.

The prefix “Cu-v” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount±10%. In other embodiments, the term “about” includes theindicated amount±5%. In certain other embodiments, the term “about”includes the indicated amount±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Amino” refers to a NH₂ group or the group —NR^(y)R^(z) wherein R^(y)and R^(z) are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein.

“Alkyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double bonds (known as“alkenyl”) and/or triple bonds (known as “alkynyl”)), having from one totwelve carbon atoms (C₁-C₁₂ alkyl), preferably one to eight carbon atoms(C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆ alkyl), and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl,prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl,propynyl, butynyl, pentynyl, hexynyl, and the like. Unless statedotherwise specifically in the specification, an alkyl group may beoptionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to thegroup through a single or double bond. The points of attachment of thealkylene chain to the rest of the molecule and to the group can bethrough one carbon or any two carbons within the chain. Unless statedotherwise specifically in the specification, an alkylene chain may beoptionally substituted.

“Alkylcarbonyl” refers to a group of the formula —(C═O)R_(a) where R_(a)is an alkyl group as defined above containing one to twelve carbonatoms. Unless stated otherwise specifically in the specification, analkylcarbonyl group is optionally substituted.

“Alkoxy” refers to a group of the formula —OR where R is an alkyl groupas defined above containing one to twelve carbon atoms. A “haloalkoxy”is an alkoxy group as defined above, wherein at least onecarbon-hydrogen bond is replaced with a carbon-halogen bond. Unlessstated otherwise specifically in the specification, an alkoxy orhaloalkoxy group may be optionally substituted.

“Alkoxyalkyl” refers to a group of the formula —R^(b)OR^(a) where R^(a)is an alkyl group as defined above containing one to twelve carbon atomsand R_(b) is an alkylene group as defined above. A “haloalkoxyalkyl”group is an alkoxyalkyl, wherein at least one carbon-hydrogen bond isreplaced with a carbon-halogen bond. Unless stated otherwisespecifically in the specification, an alkoxyalkyl or haloalkoxyalkylgroup may be optionally substituted.

“Alkoxycarbonyl” refers to a group of the formula —(C═O)OR^(a) whereR^(a) is an alkyl group as defined above containing one to twelve carbonatoms. Unless stated otherwise specifically in the specification, analkoxycarbonyl group is optionally substituted.

“Alkoxycarbonylalkyl” refers to a group of the formula —R^(b)(C═O)OR^(a)where R^(a) is an alkyl group as defined above and R^(b) is an alkyleneas defined above. Unless stated otherwise specifically in thespecification, an alkoxycarbonylalkyl group is optionally substituted.

“Alkylthio” refers to the group “alkyl-S—”.

“Aminocarbonyl” refers to a group of the formula —(C═O)N(R^(a))₂, whereeach R^(a) is independently H or an alkyl group as defined above. Unlessstated otherwise specifically in the specification, an aminocarbonylgroup is optionally substituted.

“Aminoalkyl” refers to the group “-alkyl-NR^(y)R^(z),” wherein R^(y) andR^(z) are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Alkylsulfonyl” refers to a group of the formula —S(O)₂R^(a) where R^(a)is an alkyl group as defined above. Unless stated otherwise specificallyin the specification, an alkylsulfonyl group may be optionallysubstituted.

“Alkylsulfonylalkyl” refers to a group of the formula —R^(b)S(O)₂R^(a)where R^(a) is an alkyl group as defined above and R is an alkylenegroup as defined above. Unless stated otherwise specifically in thespecification, an alkylsulfonylalkyl group may be optionallysubstituted.

“Acyl” refers to a group —C(O)R^(y), wherein R^(y) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethyl-carbonyl and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein, or R^(y) and R^(z) are taken together to form a cycloalkyl orheterocyclyl; each of which may be optionally substituted, as definedherein.

“Amidino” refers to —C(NR^(y))(NR^(z) ₂), wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Aryl” refers to a hydrocarbon ring system group comprising hydrogen, 6to 18 carbon atoms and at least one aromatic ring. For purposes of thisdisclosure, the aryl group may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl groups include, but are not limited to, aryl groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl groups thatare optionally substituted. “Arylalkyl” or “Aralkyl” refers to the group“aryl-alkyl-”.

“Carboxyl ester” or “ester” refer to both —OC(O)R^(x) and —C(O)OR^(x),wherein R^(x) is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroalkyl, or heteroaryl; each of which may be optionallysubstituted, as defined herein.

“Cyanoalkyl” is an alkyl group as defined above, wherein at least onecarbon-hydrogen bond is replaced with a carbon-cyano bond. Unless statedotherwise specifically in the specification, cyanoalkyl group may beoptionally substituted.

“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromaticmonocyclic or polycyclic hydrocarbon group consisting solely of carbonand hydrogen atoms, which may include fused or bridged ring systems,having from three to fifteen carbon atoms, preferably having from threeto ten carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. Monocyclic groups include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic groups include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl,and the like. Unless otherwise stated specifically in the specification,a cycloalkyl group may be optionally substituted.

“Cycloalkyloxy” is a cycloalkyl group connected to the remainder of themolecule via an oxygen atom linker. Unless otherwise stated specificallyin the specification, a cycloalkyloxy group may be optionallysubstituted.

“Cycloalkylalkyl” refers to a group of the formula —R_(b)R_(d) whereR_(b) is an alkylene chain as defined above and R_(d) is a cycloalkylgroup as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group may be optionally substituted.

“Cycloalkylalkyloxy” refers to a group of the formula —OR_(b)R_(d) whereR_(b) is an alkylene chain as defined above and R_(d) is a cycloalkylgroup as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyloxy group may be optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the disclosure. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl group, as defined above, that issubstituted by one or more halo groups, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group may be optionally substituted.

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group, provided thepoint of attachment to the remainder of the molecule is through a carbonatom. The term “heteroalkyl” includes unbranched or branched saturatedchain having carbon and heteroatoms. By way of example, 1, 2, or 3carbon atoms may be independently replaced with the same or differentheteroatomic group. Heteroatomic groups include, but are not limited to,—NR^(y)—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, wherein R^(y) ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein. Examples of heteroalkyl groups include ethers (e.g.,—CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃, etc.),thioethers (e.g., —CH₂SCH₃, —CH(CH₃)SCH₃, —CH₂CH₂SCH₃,—CH₂CH₂SCH₂CH₂SCH₃, etc.), sulfones (e.g., —CH₂S(O)₂CH₃,—CH(CH₃)S(O)₂CH₃, —CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)₂CH₂CH₂OCH₃, etc.), andamines (e.g., —CH₂NR^(y)CH₃, —CH(CH₃)NR^(y)CH₃, —CH₂CH₂NR^(y)CH₃,—CH₂CH₂NR^(y)CH₂CH₂NR^(y)CH₃, etc., where R^(y) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2heteroatoms, or 1 heteroatom.

“Hydroxylalkyl” refers an alkyl group as defined above containing one totwelve carbon atoms which has been substituted by one or more hydroxylgroups. Unless stated otherwise specifically in the specification,hydroxylalkyl group may be optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring group which consists of two to twelvecarbon atoms and from one to six heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Unless stated otherwisespecifically in the specification, the heterocyclyl group may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl group may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclyl groupmay be partially or fully saturated. Examples of such heterocyclylgroups include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification. Unless stated otherwise specifically in thespecification, a heterocyclyl group may be optionally substituted.

“C-heterocyclyl” refers to a heterocyclyl group as defined above wherethe point of attachment of the heterocyclyl group to the rest of themolecule is through a carbon atom in the heterocyclyl group. Unlessstated otherwise specifically in the specification, a C-heterocyclylgroup may be optionally substituted.

“Heterocyclylcarbonyl” refers to a group of the formula —C(═O)R_(e)where R_(e) is a heterocyclyl group as defined above. Unless statedotherwise specifically in the specification, a heterocyclycarbonyl groupmay be optionally substituted.

“Heterocyclylalkyl” refers to a group of the formula —R_(b)R_(e) whereR_(b) is an alkylene chain as defined above and R_(e) is a heterocyclylgroup as defined above. Unless stated otherwise specifically in thespecification, a heterocyclylalkyl group may be optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system group comprisinghydrogen atoms, one to thirteen carbon atoms, one to six heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur, andat least one aromatic ring. For purposes of this disclosure, theheteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclicring system, which may include fused or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl group may beoptionally oxidized; the nitrogen atom may be optionally quaternized.Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenvl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

“Heteroarylalkyl” refers to a group of the formula —R_(b)R_(e) whereR_(b) is an alkylene chain as defined above and R_(e) is a heteroarylgroup as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group may be optionally substituted.

“Imino” refers=NH substituent or to a group —C(NR^(y))R^(z), whereinR^(y) and R^(z) are ach independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. “Imido” refersto a group —C(O)NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are eachindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Oxime” refers to the group —CR^(y)(═NOH) wherein R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein.

“Sulfonyl” refers to the group —S(O)₂R^(y), where R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl,phenylsulfonyl and toluenesulfonyl.

The term “substituted” used herein means any of the above groups (e.g.,alkyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, aminylcarbonyl, aminylalkyl,alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, hydroxylalkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,haloalkyl, heterocyclyl, C-heterocyclyl, heterocyclylcarbonyl,heterocyclylalkyl, heteroaryl and/or heteroarylalkyl) wherein at leastone hydrogen atom is replaced by a bond to a non-hydrogen atoms such as,but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygenatom in groups such as hydroxyl groups, alkoxy groups, and ester groups;a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfonegroups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groupssuch as amines, amides, alkylamines, dialkylamines, arylamines,alkylarylamines, diarylamines, N-oxides, imides, and enamines; a siliconatom in groups such as trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatomsin various other groups.

“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. For example, “substituted” includes any of theabove groups in which one or more hydrogen atoms are replaced with—NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(b), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and—SO₂NR_(g)R_(h). Substituted also means any of the above groups in whichone or more hydrogen atoms are replaced with —C(═O)R_(g), —C(═O)OR_(g),—C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(R)R_(h). In the foregoing,R_(g) and R_(h) are the same or different and independently hydrogen,alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.“Substituted” further means any of the above groups in which one or morehydrogen atoms are replaced by a bond to an amino, alkylaminyl, cyano,hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylaminyl,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl group. In addition, each of theforegoing substituents may also be optionally substituted with one ormore of the above substituents.

Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in some embodiments, the term “substituted alkyl” refers toan alkyl group having one or more substituents including hydroxy, halo,alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl.In other embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl,or heteroaryl, each of which is unsubstituted.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the disclosure. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the disclosure that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the disclosure. Prodrugs are typically rapidly transformedin vivo to yield the parent compound of the disclosure, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi,T., et al., A.C.S. Symposium Series, Vol. 14, and in BioreversibleCarriers in Drug Design, Ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound of the disclosure in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of the disclosure may be prepared by modifying functionalgroups present in the compound of the disclosure in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the disclosure. Prodrugs include compounds of thedisclosure wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the disclosure isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amide derivatives of amine functional groupsin the compounds of the disclosure and the like.

This disclosure is also meant to encompass all pharmaceuticallyacceptable compounds of formula (I) being isotopically-labelled byhaving one or more atoms replaced by an atom having a different atomicmass or mass number. Examples of isotopes that can be incorporated intothe disclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I,and ¹²⁵I, respectively. These radiolabelled compounds could be useful tohelp determine or measure the effectiveness of the compounds, bycharacterizing, for example, the site or mode of action, or bindingaffinity to pharmacologically important site of action. Certainisotopically-labelled compounds of structure (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium. i.e. ³H,carbon-13, i.e. ¹³C and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof structure (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

This disclosure is also meant to encompass the in vivo metabolicproducts of the disclosed compounds. Such products may result from, forexample, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the disclosure includes compoundsproduced by a process comprising administering a compound of thisdisclosure to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabelled compound of the disclosure in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl group may or may not be substituted and that the descriptionincludes both substituted aryl groups and aryl groups having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines, suchas alkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂ (substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃) or mixed amines, etc., substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as ammonia, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, diethanolamine,ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine,glucosamine, methylglucamine, theobromine, triethanolamine,tromethamine, purines, piperazine, piperidine, N-ethylpiperidine,polyamine resins and the like. Particularly preferred organic bases areisopropylamine, diethylamine, ethanolamine, trimethylamine,dicyclohexylamine, choline and caffeine.

Often crystallizations produce a solvate of the compound of thedisclosure. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the disclosurewith one or more molecules of solvent. The solvent may be water, inwhich case the solvate may be a hydrate. Alternatively, the solvent maybe an organic solvent. Thus, the compounds of the present disclosure mayexist as a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the disclosure may be truesolvates, while in other cases, the compound of the disclosure maymerely retain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe disclosure and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

The compounds of this disclosure, or their pharmaceutically acceptablesalts or tautomers may contain one or more asymmetric centers and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids. The present disclosure ismeant to include all such possible isomers, as well as their racemic andoptically pure forms. Optically active (+) and (−), (R)- and (S)-, or(D)- and (L)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques, for example,chromatography and fractional crystallization. Conventional techniquesfor the preparation/isolation of individual enantiomers include chiralsynthesis from a suitable optically pure precursor or resolution of theracemate (or the racemate of a salt or derivative) using, for example,chiral high pressure liquid chromatography (HPLC). When the compoundsdescribed herein contain olefinic double bonds or other centres ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposcablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule, for example, the conversion of aketone to an enol via a proton shift. Tautomers are in equilibrium withone another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers. The present disclosure includestautomers of any said compounds.

2. Compounds

In one embodiment, provided is a compound of formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or a mixture ofstereoisomers, tautomer or prodrug thereof, wherein:

Z is N or CH;

R¹ is halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkyloxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,aminocarbonyl, or heterocyclylcarbonyl, wherein each is optionallysubstituted; and R⁵ is H; or

R¹ and R⁵ together with the atom to which they are attached form a5-membered ring having the structure:

Y is N or CR⁶;

R⁶ is H, halo, cyano, C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,—S(O)_(w)(C₁-C₆ alkyl), cycloalkyl, heterocyclyl, heteroaryl, aryl,acyl, or amido, wherein each is optionally substituted;

R¹⁰ is H, halo, cyano. C₁-C₆ alkyl, C₁-C₆ haloalkyl, or cycloalkyl;

R² is C₁-C₆ alkyl, cycloalkyl, cycloalkylalkyl, C₁-C₆ alkoxy,cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkoxy,amino, C₁-C₆ alkylamino, cycloalkylamino, cycloalkylalkylamino,heterocyclylamino, or heterocyclylalkylamino, wherein each is optionallysubstituted;

R^(3a) and R^(3b) are each independently H, halo, cyano, amino, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ heteroalkyl, C₁-C₆ cyanoalkyl,C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylsulfonylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aminocarbonyl,heterocyclylcarbonyl, or -L²-R⁸, wherein each is optionally substituted;

or R⁴ and either R^(3a) or R^(3b) when attached to an adjacent carbon,together with the atoms bound thereto join to form a heterocyclyl orheteroaryl, wherein each heterocyclyl or heteroaryl is optionallysubstituted;

or R^(3a) and R^(3b) when attached to an adjacent carbon, together withthe atoms bound thereto join to form a cycloalkyl, heterocyclyl, orheteroaryl, wherein each cycloalkyl, heterocyclyl, or heteroaryl isoptionally substituted;

R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆haloalkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl,C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl, heterocyclylcarbonyl, or -L¹-R⁷, wherein each isoptionally substituted;

L¹ is —S(O)_(p)—, —S(O)_(p)N(R⁹)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—, or—C(O)N(R⁹)—:

each L² is independently —O—, —S(O)_(m)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—,—OC(O)—, —C(O)N(R⁹)—, —N(R⁹)C(O)—, —N(R⁹)C(O)—, —OC(O)N(R⁹)—,—N(R⁹)C(O)N(R⁹)—, —S(O)_(p)N(R⁹)—, —N(R⁹)S(O)_(p)N(R⁹)—, or—N(R⁹)S(O)₉—;

R⁷ is C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,wherein each is optionally substituted;

each R⁸ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl, wherein each is optionallysubstituted;

each R⁹ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂₋₆ alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl:

each p is independently 1 or 2;

each w is independently 0, 1 or 2; and

each m is independently 0, 1, 2 or 3;

provided that:

a) when R⁵ is H, then Z is N, and R² is C-heterocyclyl, which isoptionally substituted; andb) when R¹ and R⁵ together with the atom to which they are attached formthe 5-membered ring, then either:

i) R² is C₁-C₆ alkoxy, cycloalkyloxy, cycloalkylalkyloxy,heterocyclyloxy, heterocyclylalkyloxy, amino, C₁-C₆ alkylamino,cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, orheterocyclylalkylamino; Z is N; R⁵ is H; Y is N or CR⁶; and R⁶ is halo,C₁-C₆ haloalkyl or cycloalkyl; or

ii) R² is C₁-C₆ alkyl, cycloalkyl or cycloalkylalkyl, wherein each isoptionally substituted.

In one embodiment, provided is a compound of formula (II):

or a pharmaceutically acceptable salt, prodrug, stereoisomer, or amixture of stereoisomers thereof, wherein:

R⁴¹ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R⁴⁵;

R⁴² is:

-   -   a fused bicyclic ring system having a heterocyclyl or cycloalkyl        fused to a heteroaryl, wherein the ring system is attached to        the remainder of the molecule via the heterocyclyl or cycloalkyl        and the ring system is independently optionally substituted with        one or more halo, cyano, C₁₋₆ alkyl. C₁₋₆ haloalkyl, C₁₋₆        alkoxy, amino, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆        cyanoalkyl, C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆        alkylene-S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —C₁₋₆        alkylene-C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C₁₋₆ alkylene-SO₂NR⁴⁶R⁴⁷, —C₁₋₆        alkylene-NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —C₁₋₆        alkylene-C(O)R⁴⁶, —C₁₋₆ alkylene-OC(O)R⁴⁶, —C₁₋₆        alkylene-C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, —C₁₋₆        alkylene-O—C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)OR⁴⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ alkoxyalkyl substituted with one or more substituents        independently selected from halo, amino, cyano, hydroxy, C₁₋₆        haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆        alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷,        —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        aryl, arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ haloalkyl substituted with one or more substituents        independently selected from amino, cyano, hydroxy, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl,        —S(O)₂(C₁₋₆ alkyl), —C(O)N⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,        —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   C₁₋₆ cyanoalkyl optionally substituted with one or more        substituents independently selected from halo, amino, hydroxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —S(O)₂(C₁₋₆ alkyl),        —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶,        —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₃₋₁₀ cycloalkyl substituted with one or more substituents        independently selected from amino, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆        alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆        hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted with one or more        halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl, wherein the        heterocyclyl, heteroaryl, or heteroarylalkyl are optionally        substituted with one or more substituents independently selected        from C₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo; or    -   —X—C(R⁴⁸)(R⁴⁹)(R), wherein:        -   X is C₁₋₆ alkylene optionally substituted with one or more            halo;        -   R⁴⁸ and R⁴⁹, together with the carbon atom to which they are            attached, form an optionally substituted C₃₋₁₀ cycloalkyl;            and        -   R⁵⁰ is cyanoalkyl, C₁₋₆ alkoxyalkyl, C₂₋₆ alkenyl,            C₂₋₆alkynyl, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆            hydroxyalkyl, C₁₋₆ alkoxyalkyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,            heteroaryl, or heteroarylalkyl;

R^(43a) and R^(43b) are each independently H, halo, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl,C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl),cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, amido, or —C(O)R⁴⁵;

R⁴⁴ is cycloalkyl, C₁₋₆ heterocyclyl, —N(R₅₁)₂, —OR⁵¹, or —SR₅₁;

each R⁴⁵ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R⁵²)₂, orheterocyclyl, wherein each C₁₋₆ alkyl, C₁₋₆ alkoxy, or heterocyclyl isoptionally substituted;

each R⁴⁶ and R⁴⁷ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl,wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionallysubstituted:

each R⁵¹ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl. C₁₋₆ alkoxyalkyl. C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl,—C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆cycloalkyl optionally substitutedwith one or more C₁₋₆ alkyl, C₃₋₆ cycloalkylalkyl optionally substitutedwith one or more C₁₋₆ alkyl, heterocyclyl optionally substituted withone or more R⁵³, or heterocyclylalkyl optionally substituted with one ormore R⁵³; or

two R⁵¹, together with the nitrogen to which they are attached, form athree- to six-membered heterocyclyl optionally substituted with one ormore R⁵³;

each R⁵² is independently H or optionally substituted C₁₋₆ alkyl;

each R⁵³ is independently C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, oxo, C₁₋₆alkoxy, amino, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ alkoxyalkyl, cyano,heterocyclyl, heterocyclylalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl,C₃₋₆ cycloalkylsulfonyl, —C(O)R⁵⁴, or —C₁₋₆ alkylene-C(O)R⁵⁴;

each R⁵⁴ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, amino optionallysubstituted with halo, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, hydroxy, C₁₋₆alkoxyalkyl, C₁₋₆ cyanoalkyl, —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆aminoalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl, heterocyclyl, orheterocyclylalkyl; and

provided that when R⁴⁴ is cycloalkyl, —N(R⁵¹)₂, or —OR⁵¹, then R⁴² isnot an unsubstituted C₁₋₆ cyanoalkyl.

In some embodiments, are provided compounds having activity as LRRK2inhibitors, the compounds are of formula (A-I):

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer, or prodrug thereof, wherein:

-   -   Cy is optionally substituted cycloalkyl or optionally        substituted C-heterocyclyl;    -   R¹¹ is halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,        cycloalkylalkyloxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,        aminocarbonyl or heterocyclylcarbonyl;    -   R¹² is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl,        C₁-C₆ alkoxyalkyl, C₁-C₆ haloalkoxyalkyl C₁-C₆ cyanoalkyl, C₁-C₆        aminoalkyl, C₁-C₆ alkylsulfonyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,        heteroarylylalkyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl,        C₁-C₆ alkoxycarbonylalkyl, aminocarbonyl or        heterocyclylcarbonyl, wherein each C₁-C₆ alkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        heteroaryl, or heteroarylalkyl is optionally substituted; and    -   R^(13a) and R^(13b) are each independently H, halo, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl,        C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆        alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆        alkoxycarbonyl, aminocarbonyl or heterocyclylcarbonyl, wherein        each C₁-C₆ alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl is        optionally substituted    -   or R¹² and either R^(13a) or R^(13b) when attached to an        adjacent carbon, together with the atoms bound thereto join to        form a heterocyclyl or heteroaryl which is optionally        substituted.

In some embodiments, the compounds are of formula (A-I) or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer, or prodrug thereof, wherein:

-   -   Cy is optionally substituted cycloalkyl or optionally        substituted C-heterocyclyl;    -   R¹¹ is halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,        cycloalkylalkyloxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,        aminocarbonyl or heterocyclylcarbonyl;    -   R¹² is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl,        C₁-C₆ alkoxyalkyl, C₁-C₆ haloalkoxyalkyl C₁-C₆ cyanoalkyl, C₁-C₆        aminoalkyl, C₁-C₆ alkylsulfonyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,        heteroarylylalkyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl,        C₁-C₆ alkoxycarbonylalkyl, aminocarbonyl or        heterocyclylcarbonyl, wherein each C₁-C₆ alkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        heteroaryl, or heteroarylalkyl is optionally substituted; and    -   R^(13a) and R^(13b) are each independently H, halo, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl,        C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆        alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆        alkoxycarbonyl, aminocarbonyl or heterocyclylcarbonyl, wherein        each C₁-C₆ alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl is        optionally substituted.

In some embodiments, the compounds are of compounds having activity asLRRK2 inhibitors, the compounds of formula (A-I) or a pharmaceuticallyacceptable salt, stereoisomer, tautomer or prodrug thereof, wherein:

-   -   Cy is cycloalkyl or C-heterocyclyl;    -   R¹¹ is halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,        cycloalkylalkyloxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,        aminylcarbonyl or heterocyclylcarbonyl;    -   R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl,        C₁-C₆ alkoxyalkyl, C₁-C₆ haloalkoxyalkyl C₁-C₆ cyanoalkyl, C₁-C₆        aminylalkyl, C₁-C₆ alkylsulfonyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,        heteroarylylalkyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl,        C₁-C₆ alkoxycarbonylalkyl, aminylcarbonyl or        heterocyclylcarbonyl; and    -   R^(13a) and R^(13b) are each independently H, halo, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl,        C₁-C₆ cyanoalkyl, C₁-C₆ aminylalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆        alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl. C₁-C₆ alkylcarbonyl, C₁-C₆        alkoxycarbonyl, aminylcarbonyl or heterocyclylcarbonyl.

In some embodiments, the compounds are of compounds having activity asLRRK2 inhibitors, the compounds of formula (A-I) or a pharmaceuticallyacceptable salt, stereoisomer, tautomer or prodrug thereof, wherein:

-   -   R¹² is:    -   a fused bicyclic ring system having a heterocyclyl or cycloalkyl        fused to a heteroaryl, wherein the ring system is attached to        the remainder of the molecule via the heterocyclyl or cycloalkyl        and the ring system is independently optionally substituted with        one or more halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, amino, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆        cyanoalkyl, C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆        alkylene-S(O)₂(C₁₋₆ alkyl), —C(O)NR¹⁶R¹⁷, —NR¹⁶C(O)R¹⁷, —C₁₋₆        alkylene-C(O)NR¹⁶R¹⁷, —C₁₋₆ alkylene-NR¹⁶C(O)R¹⁷, —SO₂NR¹⁶R¹⁷,        —NR¹⁶SO₂R¹⁷, —C₁₋₆ alkylene-SO₂NR¹⁶R¹⁷, —C₁₋₆        alkylene-NR¹⁶SO₂R¹⁷, —C(O)R¹⁶, —OC(O)R¹⁶, —C(O)₂R¹⁶, —C₁₋₆        alkylene-C(O)R¹⁶, —C₁₋₆ alkylene-OC(O)R¹⁶, —C₁₋₆        alkylene-C(O)₂R¹⁶, —O—C(O)NR¹⁶R¹⁷, —NR¹⁶C(O)OR¹⁷, —C₁₋₆        alkylene-O—C(O)NR¹⁶R¹⁷, —C₁₋₆ alkylene-NR¹⁶C(O)OR¹⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl.    -   C₁₋₆ alkoxyalkyl substituted with one or more substituents        independently selected from halo, amino, cyano, hydroxy, C₁₋₆        haloalkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆        alkyl), —C(O)NR¹⁶R¹⁷, —NR¹⁶C(O)R¹⁷, —SO₂NR¹⁶R¹⁷, —NR¹⁶SO₂R¹⁶,        —C(O)R¹⁶, —OC(O)R¹⁶, —C(O)₂R¹⁶, —O—C(O)NR¹⁶R¹⁷, —NR¹⁶C(O)OR¹⁷,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        aryl, arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ haloalkyl substituted with one or more substituents        independently selected from amino, cyano, hydroxy, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl,        —S(O)₂(C₁₋₆ alkyl), —C(O)NR¹⁶R¹⁷, —NR¹⁶C(O)R¹⁷, —SO₂NR¹⁶R¹⁷,        —NR¹⁶SO₂R¹⁷, —C(O)R¹⁶, —OC(O)R¹⁶, —C(O)₂R¹⁶, —O—C(O)NR¹⁶R¹⁷,        —NR¹⁶C(O)OR¹⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   C₁₋₆ cyanoalkyl optionally substituted with one or more        substituents independently selected from halo, amino, hydroxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, —S(O)₂(C₁₋₆ alkyl),        —C(O)NR¹⁶R¹⁷, —NR¹⁶C(O)R¹⁷, —SO₂NR¹⁶R¹⁷, —NR¹⁶SO₂R¹⁷, —C(O)R¹⁶,        —OC(O)R¹⁶, —C(O)₂R¹⁶, —O—C(O)NR¹⁶R¹⁷, —NR¹⁶C(O)OR¹⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₃₋₁₀ cycloalkyl substituted with one or more substituents        independently selected from amino, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆        alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆        hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted with one or more        halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl, wherein the        heterocyclyl, heteroaryl, or heteroarylalkyl are optionally        substituted with one or more substituents independently selected        from C₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo; or    -   —X²—C(R¹⁸)(R¹⁹)(R²⁰), wherein:    -   X² is C₁₋₆ alkylene optionally substituted with one or more        halo;    -   R¹⁸ and R¹⁹, together with the carbon atom to which they are        attached, form an optionally substituted C₃₋₁₀ cycloalkyl; and    -   R²⁰ is cyanoalkyl, C₁₋₆ alkoxyalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl,        —S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆        alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   provided that when Cy is cycloalkyl, then R¹² is not an        unsubstituted C₁₋₆ cyanoalkyl,

In some embodiments, the compound is of formula (A-Ia):

In some embodiments, the compound is of formula (A-Ib):

In some embodiments, Cy is optionally substituted with 1 to 3substitutents. In some embodiments, the optional substituentsindependently are halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl,C₁-C₆ alkylsulfonyl, C₁-C₆ alkylsulfonylalkyl, C₁-C₆ alkylsulfonylalkyl,cycloalkyl, cycloalkylalkyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl,aminocarbonyl or heterocyclylcarbonyl. In some embodiments, Cy isoptionally substituted with halo. In some embodiments, Cy is optionallysubstituted with fluoro.

In some embodiments, Cy is optionally substituted cycloalkyl. In someembodiments, Cy is substituted with halo. In some embodiments, Cy issubstituted with fluoro. In some embodiments, Cy is cycloalkyl.

In some embodiments, the compound is of formula (A-Ic):

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer, or prodrug thereof, wherein:

R¹¹ is chloro or —CF₃;

R¹² is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆alkoxyalkyl, C₁-C₆ haloalkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl,C₁-C₆ alkylsulfonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl or heterocyclylcarbonyl, wherein each C₁-C₆ alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, or heteroarylalkyl is optionally substituted; and

one of R^(13a) and R^(13b) is H, and the other of R^(13a) and R^(13b) isH, halo, or methyl.

In some embodiments, the compound is of formula (A-I′):

wherein:

-   -   x¹ and y¹ are each independently 1, 2 or 3:    -   R^(14a) and R^(14b) are, at each occurrence, independently        either:    -   (a) H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl,        C₁-C₆ alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆        alkylsulfonyl, C₁-C₆ alkylsulfonylalkyl, C₁-C₆        alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, C₁-C₆        alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aminocarbonyl or        heterocyclylcarbonyl, or    -   (b) R^(14a) is H, halo, cyano or C₁-C₆ alkyl, and R^(14b)        together with the carbon atom to which it is bound is taken        together with an adjacent R^(14b) and the carbon atom to which        it is bound to form a carbon-carbon double bond.

In some embodiments, the compound is of formula (A-I′a):

In some embodiments, the compound is of formula (A-I′b):

In some embodiments, Cy is saturated or unsaturated cyclopropyl,cyclobutyl or cyclopentyl. In some embodiments, cyclopropyl, cyclobutylor cyclopentyl is optionally substituted. In some embodiments, Cy iscyclopropyl or cyclopent-1-en-1-yl.

In some embodiments, Cy is cyclopropyl, cyclopent-1-en-1-yl,cyclopentyl, cyclobutyl, trans-2-fluorocyclopropan-1-yl, or1-fluorocyclopropan-1-yl.

In some embodiments, Cy is C-heterocyclyl. In one embodimentC-heterocyclyl is optionally substituted. In some embodiments, Cy is1-methyl-1H-pyrazol-4-yl.

In some embodiments, the compound is of formula (A-I″):

wherein:

-   -   A is O or NR¹⁵; x² is 1, 2, 3, or 4; y² is 0, 1, 2, or 3;    -   R^(14a) and R^(14b) are, at each occurrence, independently        either:    -   (a) H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl,        C₁-C₆ alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆        alkylsulfonyl, C₁-C₆ alkylsulfonylalkyl, C₁-C₆        alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, C₁-C₆        alkylcarbonyl, C₁-C₆ alkyloxycarbonyl, aminocarbonyl or        heterocyclylcarbonyl, or    -   (b) R^(14a) is H, halo, cyano or C₁-C₆ alkyl, and R^(14b)        together with the carbon atom to which it is bound is taken        together with an adjacent R^(4b) and the carbon atom to which it        is bound to form a carbon-carbon double bond; and    -   R¹⁵ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl,        C₁-C₆ alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆        alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, C₁-C₆        alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aminocarbonyl or        heterocyclylcarbonyl.

In some embodiments, the compound is of formula (A-I″a):

In some embodiments, the compound is of formula (A-I″b):

In some embodiments, R¹¹ is halo, cyano, C₁-C₆ alkyl or C₁-C₆ haloalkyl.In some embodiments, R¹¹ is C₁-C₆ haloalkyl. In some embodiments, C₁-C₆haloalkyl is C₁-C₆ fluoroalkyl. In some embodiments, C₁-C₆ haloalkyl istrifluoromethyl.

In some embodiments, R¹¹ is cyano. In some, R¹¹ is halo. In someembodiments, halo is chloro.

In some embodiments, R¹² is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl,C₁-C₆ alkylsulfonyl, cycloalkyl, heterocyclyl, heteroaryl wherein eachcycloalkyl, heterocyclyl, or heteroaryl is optionally substituted. Insome embodiments. R¹² is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ cyanoalkyl or C₁-C₆ aminylalkyl.In some embodiments, R² is selected from methyl, ethyl, isopropyl,2-methylprop-1-yl, 1-methylethyl, sulfonylmethyl, cyclopentyl,cyclopropyl, cyclobutyl, bicyclo[3.1.0]hexanyl, oxetanyl,tetrahydropyranyl, piperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl,6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl,6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, or1H,4H,5H,6H-cyclopenta[c]pyrazolyl.

In some embodiments, R¹² is C₁-C₆ cyanoalkyl. In some embodiments, R¹¹is 2-cyano-prop-2-yl.

In some embodiments, R¹² is heteroaryl or heteroarylalkyl. For examplein some embodiments, R¹² is heteroarylalkyl, for example a 5-membered,nitrogen containing heteroarylalkyl. In some embodiments, R¹² istriazolylalkyl, for example2-methyl-2-(1-methyl-1H-1,2,4-triazol-3-yl)propanyl.

In some embodiments, R² may be substituted with 1-3 groups independentlyselected from deuterium, halo, hydroxy, cyano, C₁-C₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, and acyl, aminoacyl. Each of theforegoing groups may also be further substituted halo, C₁-C₆ alkyl andC₁-C₆ haloalkyl. In some embodiments, R¹² may be substituted with 1-3groups independently selected from fluoro, hydroxy, morpholinylmethyl,methyl, ethyl, deuterium, pyrazolyl, pyrrolyl, 1,2,4-triazolyl,1,2,3-triazolyl, 1-ethyl-1,2,4-triazolyl, 1-methylpyrazolyl,1-methylimidazolyl, 1-difluoromethyl-1,2,4-triazolyl,2-difluoromethyl-1,2,4-triazolyl, 2-methyloxadiazolyl,1-methyl-1,2,4-triazolyl, 2-methyl-1,2,4-triazolyl, acyl, or oxetanyl.

In some embodiments, R¹² is:

In some embodiments, one of R^(13a) or R^(13b) is H, and the other ofR^(13a) or R^(13b) is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl,cycloalkyl, cycloalkylalkyl, C₁-C₆ alkylcarbonyl, C₁-C₆alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl. In someembodiments, one of R^(13a) or R^(13b) is halo, C₁-C₆ alkyl or C₁-C₆cyanoalkyl. In some embodiments R^(13a) is H and R^(13b) is halo, C₁-C₆alkyl or C₁-C₆ cyanoalkyl. In some embodiments, R^(13b) is H and R^(13a)is halo, C₁-C₆ alkyl or C₁-C₆ cyanoalkyl. In some embodiments, C₁-C₆alkyl is methyl. In some embodiments, C₁-C₆ cyanoalkyl is2-cyano-prop-2-yl.

In some embodiments, the compound is selected from a compound in TableA-1. In various different embodiments, the compound has one of thestructures set forth in Table A-1 below. The compounds in Table A-1 wereeach prepared and analyzed by mass spectrometry, liquid chromatography,and/or ¹H NMR. General methods by which the compounds may be preparedare provided below and in the Examples. Compounds in the examples werenamed by using either ChemBioDraw Ultra 13.0 or Chemaxon.

TABLE A-1 Exemplary Compounds

A-1

A-2

A-3

A-4

A-5

A-6

A-7

A-8

A-9

A-10

A-11

A-12

A-13

A-14

A-15

A-16

A-17

A-18

A-19

A-20

A-21

A-22

A-23

A-24

A-25

A-26

A-27

A-28

A-29

A-30

A-31

A-32

A-33

A-34

A-35

A-36

A-37

A-38

A-39

A-40

A-41

A-42

A-43

A-44

A-45

A-46

A-47

A-48

A-49

A-50 Second eluting isomer

A-51

A-52

A-53

A-54

A-55

A-56

A-57

A-58

A-59

A-60

A-61

A-62

A-63

A-64

A-65

A-66

A-67

A-68

A-69

A-70

A-71

A-72

A-73

A-74

A-75

A-76

A-77

A-78

A-79 Second eluting isomer

A-80

A-81

A-82

A-83 First eluting isomer

A-86

A-85 Third eluting isomer

A-87

A-89

A-90 Second eluting isomer

A-88

A-91 Fourth eluting isomer

A-92

A-84 Fourth eluting isomer

A-93

A-94

A-95 Second eluting isomer

A-96

A-97 Second eluting isomer

indicates data missing or illegible when filed

Specific stereoisomers and regioisomers contemplated include thefollowing in Table A-IA.

TABLE A-1A

Also provided herein is a method of preparing a compound of formula(A-I), comprising coupling a compound of formula (A-a), comprisingcoupling a compound of formula (A-b):

wherein X is halogen, with a compound of formula (A-b):

under conditions to provide the compound of formula (A-I).

As noted above, in one embodiment of the present disclosure, providedare LRRK2 inhibitors of formula (B-I):

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer or prodrug thereof, wherein:

Y is N or CR²¹;

R²¹ is halo, C₁-C₆ haloalkyl or cycloalkyl;

R²² is C₁-C₆ alkoxy; cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,heterocyclylalkyloxy, amino, C₁-C₆ alkylamino, cycloalkylamino,cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino;

R^(23a) and R^(23b) are each independently H, halo, cyano, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl; and

R²⁴ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl,C₁-C₆ alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, heteroarylylalkyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl or heterocyclylcarbonyl.

In one embodiment of the present disclosure, provided are LRRK2inhibitors of formula (B-I), or a pharmaceutically acceptable salt,stereoisomer, tautomer or prodrug thereof, wherein:

Y is N or CR²¹:

R²¹ is halo:

R²² is C₁-C₆ alkoxy; cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,heterocyclylalkyloxy, amino, C₁-C₆ alkylamino, cycloalkylamino,cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino;

R^(23a) and R^(23b) are each independently H, halo, cyano, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl; and

R²⁴ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁₋₆ hydroxylalkyl, C₁-C₆alkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl,C₁-C₆ alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, heteroarylylalkyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl or heterocyclylcarbonyl.

In some embodiments, provided is a compound of formula (B-Ia):

In some embodiments, provided is a compound of formula (B-Ib):

In some embodiments, Y is N. In other embodiments A is CR²¹. In someembodiments, R²¹ is chloro. In other embodiments, R²¹ is fluoro.

In some embodiments, R²¹ is C₁-C₆ haloalkyl. In other embodiments, R²¹is —CF₃. In other embodiments, R¹ is cycloalkyl. In other embodiments,R²¹ is cyclopropyl.

In some embodiments, R²² is C₁-C₆ alkoxy or C₁-C₆ alkylamino. In someembodiments, R²² is C₁-C₆ alkoxy. In some embodiments, R² is methoxy orethoxy. In some embodiments, R²² is C₁-C₆ alkylamino. In someembodiments R²² is methylamino or ethylamino.

In some embodiments, one of R^(23a) or R^(23b) is H, and the other ofR^(23a) or R^(23b) is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl,cycloalkyl, cycloalkylalkyl. C₁-C₆ alkylcarbonyl, C₁-C₆alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl. In someembodiments, R^(23a) or R^(23b) is C₁-C₆ alkyl. In some embodiments,R^(23a) is H and R^(23b) is C₁-C₆ alkyl. In some embodiments, R^(23b) isH and R^(23a) is C₁-C₆ alkyl. In some embodiments, C₁-C₆ alkyl ismethyl.

In some embodiments, R²⁴ is C₁-C₆ alkyl. In some embodiments, C₁-C₆alkyl is methyl. In some embodiments, R²⁴ is C₁-C₆ cyanoalkyl. In someembodiments, R²⁴ is 2-cyano-prop-2-yl.

In various different embodiments, the compound has one of the structuresset forth in Table B-1 below. The compounds in Table B-1 were eachprepared and analyzed by mass spectrometry, liquid chromatography,and/or ¹H NMR. General methods by which the compounds may be preparedare provided below and in the Examples.

TABLE B-1 B-1

B-2

B-3

B-4

B-5

B-6

B-7

B-8

B-9

B-10

B-11

B-12

B-13

B-14

Also provided herein is a method of preparing a compound of formula(B-I), comprising coupling a compound of formula (B-a), wherein PG is anoptional protecting group and X is halogen:

with a compound of formula (B-b):

under conditions to provide the compound of formula (B-I).

In one embodiment, provided is a compound of Formula (C-I):

or a pharmaceutically acceptable salt, stereoisomer, or a mixture ofstereoisomers, tautomer or prodrug thereof, wherein:

Y is N or CR³⁶;

Z is N or CH;

R³¹ is C₁-C₆ alkyl, cycloalkyl or cycloalkylalkyl, each of which isoptionally substituted;

R³² is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L³-R⁷, wherein eachC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted;

R³³ and R³⁴ are each independently H, halo, cyano, amino. C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, or -L⁴-R³⁸, wherein each C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted; or

or R₃₃ and R³⁴ together with the atom to which they are attached form acycloalkyl, heterocyclyl or heteroaryl, wherein each cycloalkyl,heterocyclyl, and heteroaryl is optionally substituted;

or R³² and R³³ together with the atom to which they are attached form aheterocyclyl or heteroaryl, wherein each heterocyclyl and heteroaryl isoptionally substituted:

R³⁵ is H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or cycloalkyl;

R³⁶ is H, halo, cyano, C₁-C₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁-C₆alkoxy, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,—S(O)_(w)(C₁-C₆ alkyl), cycloalkyl, heterocyclyl, heteroaryl, aryl,acyl, or amido, wherein each alkyl, alkoxyl, haloalkyl, alkoxyalkyl,cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl, or amido areindependently optionally substituted:

L³ is —S(O)_(p)—, —S(O)_(p)N(R⁹)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—, or—C(O)N(R³⁹)—;

each L⁴ is independently —O—, —S(O)_(w)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—,—OC(O)—, —C(O)N(R³⁹)—, —N(R³⁹)C(O)—, —N(R⁹)C(O)—, —OC(O)N(R³⁹)—,—N(R³⁹)C(O)N(R³⁹)—, —S(O)_(p)N(R³⁹)—, —N(R³⁹)S(O)_(p)N(R³⁹)— or—N(R³⁹)S(O)_(p)—;

R³⁷ is C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl is optionally substituted;

each R³⁸ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl, wherein each C₁-C₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl isoptionally substituted;

each R³⁹ is independently H, C₁-C₆ alkyl, C²⁻⁶ alkenyl, C₂₋₆ alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl;

each p is independently 1 or 2;

each w is independently 0, 1, or 2; and

each m is independently 0, 1, 2, or 3.

In certain embodiments, provided is a compound of Formula (C-I), or apharmaceutically acceptable salt, stereoisomer, or a mixture ofstereoisomers, tautomer or prodrug thereof, wherein:

Y is N or CR³⁶:

Z is N or CH;

R³¹ is C₁-C₆ alkyl, cycloalkyl, or cycloalkylalkyl;

R³² is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, or -L³-R³⁷, wherein each C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted;

R³³ and R³⁴ are each independently H, halo, cyano, amino, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, or -L⁴-R³⁸, wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted; or

or R³³ and R³⁴ together with the atom to which they are attached form acycloalkyl, heterocyclyl or heteroaryl, wherein each cycloalkyl,heterocyclyl, and heteroaryl is optionally substituted;

or R³² and R³³ together with the atom to which they are attached form aheterocyclyl, or heteroaryl, wherein each heterocyclyl, and heteroarylis optionally substituted;

R³⁵ is H, halo, cyano. C₁-C₆ alkyl, C₁-C₆ haloalkyl, or cycloalkyl;

R³⁶ is H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,—S(O)₂(C₁-C₆ alkyl), cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl,or amido;

L³ is —S(O)₂—, —C(O)—, —C(O)O—, or —C(O)N(R³⁹)—;

each L⁴ is independently —O—, —S—, —S(O)₂—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R³⁹)—, or —N(R³⁹)C(O)—:

R³⁷ is C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl, wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl,C₁-C₆ alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl isoptionally substituted;

each R³⁸ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl, wherein each C₁-C₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl isoptionally substituted; and

each R³⁹ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂₋₆ alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl.

Also provided is a comp und having the formula (C-Ia):

Also provided is a compound having the formula (C-Ib):

Also provided is a compound having the formula (C-Ic):

Also provided is a compound having the formula (C-Id):

Also provided is a compound having the formula (C-Ie):

Also provided is a compound having the formula (C-If):

In one embodiment, R³¹ is cycloalkyl. In certain embodiments, R³¹ iscyclopropyl.

In one embodiment. R³² is C₁-C₆ alkyl optionally substituted with one ormore halo, cyano, cycloalkyl, haloalkoxy, or optionally substitutedheteroaryl, or cycloalkyl, optionally substituted with one or more C₁-C₆alkyl. In one embodiment. R³² is C₁-C₆ alkyl, C₁-C₆ haloalkyl,cycloalkylalkyl, or C₁-C₆ cyanoalkyl. In one embodiment, R³² isoptionally substituted C₁-C₆ alkyl. In one embodiment, R³² is C₁-C₆alkyl. In one embodiment, R³² is methyl. In one embodiment, R³² isoptionally substituted cycloalkyl. In one embodiment, R³² is cycloalkyl.In one embodiment, R³² is cyclopropyl.

In one embodiment, R³² and R³³ are C₁-C₆ alkyl. In one embodiment, atleast one of R³² and R³³ are methyl.

In one embodiment, R³² and R³³ together with the atom to which they areattached form a heterocyclyl or heteroaryl, wherein each heterocyclyland heteroaryl is optionally substituted. In certain embodiments, R³²and R³³ together with the atom to which they are attached form aheterocyclyl, which is optionally substituted with cycloalkyl.

In one embodiment, R³⁴ is H.

In one embodiment, R³³ and R³⁴ together with the atom to which they areattached form a cycloalkyl, heterocyclyl or heteroaryl, wherein eachcycloalkyl, heterocyclyl and heteroaryl is optionally substituted.

In one embodiment, R³⁵ is H or optionally substituted C₁-C₆ alkyl. Inone embodiment, R³⁵ is optionally substituted C₁-C₆ alkyl. In oneembodiment, R³³ is H or C₁-C₆ alkyl. In one embodiment. R³⁵ is C₁-C₆alkyl. In one embodiment, R³⁵ is methyl. In one embodiment, R³⁵ is H. Inone embodiment, R³⁵ is H or methyl. In one embodiment, R³⁵ iscycloalkyl. In one embodiment, R³⁵ is cyclopropyl. In one embodiment,R³⁵ is cycloalkyl and R³² is cycloalkyl or cycloalkylalkyl.

In one embodiment, R³⁵ is H; one of R³³ and R³⁴ is H and the other ishalo, cyano, amino, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L⁴-R³⁸,wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted.

In one embodiment, Y is N. In one embodiment, Y is CR³⁶. In oneembodiment, R³⁶ is optionally substituted C₁-C₆ alkyl, cycloalkyl, haloor cyano. In one embodiment. R³⁶ is C₁-C₆ haloalkyl, cycloalkyl, halo orcyano. In one embodiment, R³⁶ is H, halo or cyano. In one embodiment,R³⁶ is H. In one embodiment, R³⁶ is halo. In one embodiment, R³⁶ iscyano.

In one embodiment, Z is N. In one embodiment, Z is CH.

In some embodiments, when R³² is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, R³² isoptionally substituted with one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido,amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxylester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl,haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido,hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl,alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido,thiol, thioxo, N-oxide, or —Si(R¹⁰²)₃, wherein each R¹⁰² isindependently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl.

In some embodiments, when R³² or R³³ together with the carbon atom towhich they are attached, form a heterocyclyl or heteroaryl optionallysubstituted with one or more substituents independently selected fromalkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino,aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R¹⁰²)₃, wherein each R¹⁰² is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In one embodiment, R³² or R³³ together with the carbon atom to whichthey are attached form an optionally substituted heterocyclyl. In oneembodiment, R³² or R³³ together with the carbon atom to which they areattached form an optionally substituted heterocyclyl, wherein theheterocylyl is pyrrolidinyl. In one embodiment, heterocyclyl isoptionally substituted with cycloalkyl.

In some embodiments, when R³³ or R³⁴ are each independently C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl, R³³ or R³⁴ are each independently optionally substitutedwith one or more substituents independently selected from alkyl,alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl,aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo.N-oxide, or —Si(R¹⁰²)₃, wherein each R¹⁰² is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In some embodiments, R³³ and R³⁴, together with the carbon atom to whichthey are attached, form a cycloalkyl, heterocyclyl or heteroaryloptionally substituted with one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido,amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxylester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl,haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido,hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl,alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido,thiol, thioxo, N-oxide, or —Si(R¹⁰²)₃, wherein each R¹⁰² isindependently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl.

In some embodiments, when R³⁷ is C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, arylalkyl, heteroaryl, or heteroarylalkyl, R³⁷ is optionallysubstituted with one or more substituents independently selected fromalkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino,aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R¹⁰²)₃, wherein each R¹⁰² is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In some embodiments, when R³⁸ is C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, arylalkyl, heteroaryl, or heteroarylalkyl, R³⁸ is optionallysubstituted with one or more substituents independently selected fromalkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino,aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R¹⁰²)₃, wherein each R¹⁰² is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In one embodiment, a compound may be selected from those compounds inTable C-1. Also included within the disclosure are pharmaceuticallyacceptable salt, stereoisomer, or a mixture of stereoisomers, tautomeror prodrug thereof. In certain embodiments, provided are compounds ofTable C-1 for use in the methods described herein.

TABLE C-1 C-1

C-2

C-3

C-4

C-5

C-6

C-7

C-8

C-9

C-10

C-11

C-12

C-13

C-14

C-15

C-16

C-17

C-18

C-19

C-20

C-21

C-22

C-23

C-24

C-25

C-26

C-27

C-28

C-29

C-30

C-31

C-32

C-33

C-34

C-35

C-36

C-37

C-38

C-39

C-40

C-41

C-42

C-43

C-44

C-45

C-46

C-47

C-48

C-49

C-50

C-51

C-52

C-53

C-54

C-55

In another embodiment, provided is a method for preparing a compound offormula (C-1), comprising coupling a compound of formula (C-a):

with a compound of formula (C-b):

under conditions to provide the compound of formula (C-I), wherein R isnitro or an optionally protected amino, and LG is a leaving group.

In one embodiment, provided is a compound of Formula (D-I):

or a pharmaceutically acceptable salt, prodrug, stereoisomer, or amixture of stereoisomers thereof, wherein:

R⁴¹ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R⁴⁵;

R⁴² is:

-   -   a fused bicyclic ring system having a heterocyclyl or cycloalkyl        fused to a heteroaryl, wherein the ring system is attached to        the remainder of the molecule via the heterocyclyl or cycloalkyl        and the ring system is independently optionally substituted with        one or more halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, amino, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆        cyanoalkyl, C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆        alkylene-S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —C₁₋₆        alkylene-C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C₁₋₆ alkylene-SO₂NR⁴⁶R⁴⁷,        —C₁₋₆alkylene-NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —C₁₋₆        alkylene-C(O)R⁴⁶, —C₁₋₆ alkylene-OC(O)R⁴⁶, —C₁₋₆        alkylene-C(O)₂R⁴⁶, —O—C(O)N⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, —C₁₋₆        alkylene-O—C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)OR⁴⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ alkoxyalkyl substituted with one or more substituents        independently selected from halo, amino, cyano, hydroxy, C₁₋₆        haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆        alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷,        —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        aryl, arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ haloalkyl substituted with one or more substituents        independently selected from amino, cyano, hydroxy, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, cyanoalkyl,        —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,        —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   C₁₋₆ cyanoalkyl optionally substituted with one or more        substituents independently selected from halo, amino, hydroxy,        C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —S(O)₂(C₁₋₆ alkyl),        —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶,        —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₃₋₁₀ cycloalkyl substituted with one or more substituents        independently selected from amino, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆        alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆        hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted with one or more        halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl, wherein the        heterocyclyl, heteroaryl or heteroarylalkyl are optionally        substituted with one or more substituents independently selected        from C₁₋₆ alkyl, C¹⁻⁶ haloalkyl, or halo; or    -   —X—C(R⁴⁸)(R⁴⁹)(R⁵⁰), wherein:        -   X is C₁₋₆ alkylene optionally substituted with one or more            halo;        -   R⁴⁸ and R⁴⁹, together with the carbon atom to which they are            attached, form an optionally substituted C₃₋₁₀ cycloalkyl;            and        -   R⁵⁰ is cyanoalkyl, C₁₋₆ alkoxyalkyl, C₂₋₆ alkenyl, C₂₋₆            alkynyl, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy,            C₁₋₆-hydroxyalkyl, C₁₋₄ alkoxyalkyl, cycloalkyl,            cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,            arylalkyl, heteroaryl, or heteroarylalkyl:

R^(43a) and R^(43b) are each independently H, halo, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C¹⁻⁶ alkoxyalkyl, C₁₋₆ cyanoalkyl,C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl),cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, amido, or —C(O)R⁵;

R⁴⁴ is —N(R⁵¹)₂, —OR⁵¹, or —SR⁵¹;

each R⁴⁵ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R⁵²)₂, orheterocyclyl, wherein each C₁₋₆ alkyl, C₁₋₆ alkoxy, or heterocyclyl isoptionally substituted;

each R⁴⁶ and R⁴⁷ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl,wherein each C₁₋₆ alkyl, C₁₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionallysubstituted;

each R⁵¹ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl,—C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₃₋₆ cycloalkyl optionally substitutedwith one or more C₁₋₆ alkyl, C₃₋₆ cycloalkylalkyl optionally substitutedwith one or more C₁₋₆ alkyl, heterocyclyl optionally substituted withone or more R¹³, or heterocyclylalkyl optionally substituted with one ormore R⁵³; or

two R⁵¹, together with the nitrogen to which they are attached, form athree- to six-membered heterocyclyl optionally substituted with one ormore R⁵³:

each R⁵² is independently H or optionally substituted C₁₋₆ alkyl;

each R⁵³ is independently C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, oxo, C₁₋₆alkoxy, amino, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ alkoxyalkyl, cyano,heterocyclyl, heterocyclylalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl,C₃₋₆ cycloalkylsulfonyl, —C(O)R⁵⁴, or —C₁₋₆alkylene-C(O)R⁵⁴;

each R⁵⁴ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, amino optionallysubstituted with halo, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxy, C₁₋₆alkoxyalkyl, C₁₋₆ cyanoalkyl, —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl). C₁₋₆aminoalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl, heterocyclyl, orheterocyclylalkyl; and

provided that when R⁴⁴ is —N(R⁵¹)₂ or —OR⁵¹, R⁴² is not an unsubstitutedC₁₋₆ cyanoalkyl.

In one embodiment, provided is a compound of Formula (D-I), or apharmaceutically acceptable salt, prodrug, stereoisomer, or a mixture ofstereoisomers thereof, wherein:

R⁴¹ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R⁴⁵;

R⁴² is:

-   -   a fused bicyclic ring system having a heterocyclyl or cycloalkyl        fused to a heteroaryl, wherein the ring system is attached to        the remainder of the molecule via the heterocyclyl or cycloalkyl        and the ring system is independently optionally substituted with        one or more halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, amino, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆        cyanoalkyl, C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆        alkylene-S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —C₁₋₆        alkylene-C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C₁₋₆ alkylene-SO₂NR⁴⁶R⁴⁷, —C₁₋₆        alkylene-NR⁴⁶SO₂R⁴⁷—, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶,—C₁₋₆        alkylene-C(O)R⁴⁶, —C₁₋₆ alkylene-OC(O)R⁴⁶, —C₁₋₆        alkylene-C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, —C₁₋₆        alkylene-O—C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)OR⁴⁷, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   C₁₋₆ alkoxyalkyl substituted with one or more halo, amino,        cyano, hydroxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        cyanoalkyl, —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷,        —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)⁴⁶, —C(O)₂R⁴⁶,        —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   C₁₋₆ haloalkyl substituted with amino, cyano, hydroxy, C₁₋₆        alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, cyanoalkyl,        —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,        —NR⁴⁶C(O)OR⁴—, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   C₁₋₆ cyanoalkyl optionally substituted with one or more halo,        amino, hydroxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl. C₂₋₆ alkynyl,        —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,        —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,        —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl;    -   C₃₋₁₀ cycloalkyl substituted with one or more amino. C₂₋₆        alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆        alkyl), —S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl),        C₁₋₆ haloalkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted        with one or more halo, cycloalkyl, cycloalkylalkyl,        heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;        or    -   —X—C(R⁴⁸)(R⁴⁹)(R⁵⁰), wherein:        -   X is C₁₋₆ alkylene optionally substituted with one or more            halo.        -   R⁴⁸ and R⁴⁹, together with the carbon atom to which they are            attached, form an optionally substituted C₃₋₁₀ cycloalkyl;            and        -   R⁵⁰ is cyanoalkyl, C₁₋₆ alkoxyalkyl, C₂₋₆alkenyl, C₂₋₆            alkynyl, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆            hydroxyalkyl, C₁₋₆ alkoxyalkyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,            heteroaryl, or heteroarylalkyl;

R^(43a) and R^(43b) are each independently H, halo, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl,C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl),cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, amido, or —C(O)R⁴⁵;

R⁴⁴ is —N(R⁵¹)₂, —OR⁵¹, and —SR⁵¹;

each R⁴⁵ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R⁵²)₂, orheterocyclyl, wherein each C₁₋₆ alkyl, C₁₋₆ alkoxy, or heterocyclyl isoptionally substituted;

each R⁴⁶ and R⁴⁷ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl,wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionallysubstituted:

each R⁵¹ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl. C₁₋₆ alkoxyalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl,—C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆cycloalkyl optionally substitutedwith one or more C₁₋₆ alkyl, C₃₋₆ cycloalkylalkyl optionally substitutedwith one or more C₁₋₆ alkyl, heterocyclyl optionally substituted withone or more R⁵³, or heterocyclylalkyl optionally substituted with one ormore R⁵³; or

two R⁵¹, together with the nitrogen to which they are attached, form athree- to six-membered heterocyclyl optionally substituted with one ormore R⁵³;

each R⁵² is independently H or optionally substituted C₁₋₆ alkyl;

each R⁵³ is independently C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, oxo, C₁₋₆alkoxy, amino, —S(O)₂(C₁₋₆ alkyl), C₁₋₆ alkoxyalkyl, cyano,heterocyclyl, heterocyclylalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl,C₃₋₆ cycloalkylsulfonyl, —C(O)R⁵⁴, or —C₁₋₆alkylene-C(O)R⁵⁴;

each R⁵⁴ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, amino optionallysubstituted with halo, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxy, C₁₋₆alkoxyalkyl, C₁₋₆ cyanoalkyl, —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl). C₁₋₆aminoalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl, heterocyclyl, orheterocyclylalkyl; and

provided that when R⁴⁴ is —N(R⁵¹)₂ or —OR⁵¹, R⁴² is not C₁₋₆ cyanoalkyl.

Also provided is a compound having the formula (D-Ia):

Also provided is a compound having the formula (D-Ib):

In certain embodiments, R⁴⁴ is —N(R⁵¹)₂, and each R⁵¹ is independently Hor C₁₋₆ alkyl. In certain embodiments, R⁴⁴ is —N(R⁵¹)₂, and one R⁵¹ is Hand the other R⁵¹ is C₁₋₃ alkyl.

In certain embodiments, R⁴¹ is halo, cyano, C₁₋₆ alkyl, or C₁₋₆haloalkyl. In certain embodiments, R⁴¹ is C₁₋₆ haloalkyl. In certainembodiments, R⁴¹ is C₁₋₆ fluoroalkyl. In curtain embodiments, R⁴¹ istrifluoromethyl. In certain embodiments, R⁴¹ is cyano. In certainembodiments, R⁴¹ is halo. In certain embodiments, R⁴¹ is chloro.

In certain embodiments, one of R^(43a) or R^(43b) is H, and the other ofR^(43a) or R^(4b) is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl, C₁₋₆ aminoalkyl,—S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, amido, or —C(O)R⁴⁵.

In certain embodiments, one of R⁴¹ or R^(43b) is halo, C₁₋₆ alkyl, orC₁₋₆ cyanoalkyl. In certain embodiments, R^(43a) is H, and R^(43b) ishalo, C₁₋₆ alkyl, or C₁₋₄ cyanoalkyl. In certain embodiments, C₁₋₆ alkylis methyl. In certain embodiments, C₁₋₆ cyanoalkyl is 2-cyano-prop-2-yl.

In certain embodiments, R^(43b) is hydrogen.

In certain embodiments, R⁴² is:

C₁₋₆ alkoxyalkyl substituted with one or more halo, amino, cyano,hydroxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, cyanoalkyl,—S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷. —SO₂NR⁴⁶R⁴⁷,—NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl:

C₁₋₆ haloalkyl substituted with amino, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆ alkyl),—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶,—OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl;

C₁₋₆ cyanoalkyl optionally substituted with one or more halo, amino,hydroxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, —S(O)₂(C₁₋₆ alkyl),—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶,—OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl;

C₃₋₁₀ cycloalkyl substituted with one or more amino, C₂₋₆alkenyl, C₂₋₆alkynyl, cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted with one or more halo,cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,or heteroarylalkyl; or

—X—C(R⁴⁸)(R⁴⁹)(R₅₀).

In certain embodiments, R⁴² is:

C₁₋₆ alkoxyalkyl substituted with one or more substituents independentlyselected from halo, amino, cyano, hydroxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶,—O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl;

C₁₋₆ haloalkyl substituted with one or more substituents independentlyselected from amino, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶,—O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl;

C₁₋₆ cyanoalkyl optionally substituted with one or more substituentsindependently selected from halo, amino, hydroxy, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, C₂₋₆ alkynyl, —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷,—SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶,—O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl;

C₃₋₁₀ cycloalkyl substituted with one or more substituents independentlyselected from amino, C₂₋₆ alkenyl, C₂₋₆alkynyl, cyanoalkyl, —S(C₁₋₆alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆alkyl), C₁₋₆ haloalkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl substitutedwith one or more halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl, wherein the heterocyclyl,heteroaryl or heteroarylalkyl are optionally substituted with one ormore substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, or halo; or

—X—C(R⁴⁸)(R⁴⁹)(R⁵⁰).

In certain embodiments, R⁴² is:

C₁₋₆ alkoxyalkyl substituted with one to three substituentsindependently selected from halo, amino, cyano, hydroxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆ alkyl),—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶,—OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl;

C₁₋₆ haloalkyl substituted with one to three substituents independentlyselected from amino, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶,—O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl;

C₁₋₆ cyanoalkyl optionally substituted with one to three substituentsindependently selected from halo, amino, hydroxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷,—SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶,—O—C(O)NR⁴⁶R⁴⁷. —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl;

C₃₋₁₀ cycloalkyl substituted with one to three substituentsindependently selected from amino, C₂₋₆ alkenyl, C₂₋₆ alkynyl,cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆ alkyl), —C₁₋₆alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆alkoxyalkyl substituted with one or three halo, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl, wherein the heterocyclyl, heteroaryl or heteroarylalkylare optionally substituted with one to three substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo; or

—X—C(R⁴⁸)(R⁴⁹)(R⁵⁰), wherein:

-   -   X is C₁₋₆ alkylene optionally substituted with one to three        halo;    -   R⁴⁸ and R⁴⁹, together with the carbon atom to which they are        attached, form an optionally substituted C₃₋₁₀ cycloalkyl; and    -   R⁵⁰ is cyanoalkyl, C₁₋₆ alkoxyalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl,        —S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆        alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or        heteroarylalkyl.

In certain embodiments, R⁴² is C₁₋₆ alkoxyalkyl substituted with one ormore substituents independently selected from halo, amino, cyano,hydroxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl,—S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,—NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

In certain embodiments, R⁴² is C₁₋₆ alkoxyalkyl substituted with one tothree substituents independently selected from halo, amino, cyano,hydroxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl,—S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,—NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

In certain embodiments, R⁴² is C₁₋₆ alkoxyalkyl substituted with one ormore halo. In certain embodiments, R⁴² is C₁₋₆ alkoxyalkyl substitutedwith one to three fluoro. In certain embodiments, R⁴² is C₁₋₆ haloalkylsubstituted with one or more substituents independently selected fromamino, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, cyanoalkyl, —S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷,—SO₂NR⁴⁶R⁴⁷, —NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶,—O—C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl.

In certain embodiments, R⁴² is C₁₋₆ haloalkyl substituted with one tothree substituents independently selected from amino, cyano, hydroxy,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyanoalkyl,—S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷, —SO₂NR⁴⁶R⁴⁷,—NR⁴⁶SO₂R⁴⁷, —C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

In certain embodiments, R⁴² is C₁₋₆ haloalkyl substituted with—C(O)NR⁴⁶R⁴⁷ or cyano. In certain embodiments, R⁴² is C₁₋₃ haloalkylsubstituted with —C(O)NR⁴⁶R⁴⁷. In certain embodiments, R⁴² is C₁₋₃haloalkyl substituted with cyano.

In certain embodiments, R⁴² is C₃₋₆ cycloalkyl substituted with one ormore cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆ alkyl),C₁₋₆ haloalkoxy, C₁₋₃ alkoxyalkyl substituted with one or more halo, orheteroaryl.

In certain embodiments, R⁴² is C₃₋₆ cycloalkyl substituted with one ormore substituents independently selected from cyanoalkyl, —S(C₁₋₆alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₃alkoxyalkyl substituted with one or more halo, heterocyclyl, orheteroaryl, wherein the heterocyclyl or heteroaryl is optionallysubstituted with one or more substituents independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo.

In certain embodiments, R⁴² is C₁₋₆ cycloalkyl substituted with one tothree substituents independently selected from cyanoalkyl, —S(C₁₋₆alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆ alkyl), C₁₋₄ haloalkoxy, C₁₋₃alkoxyalkyl substituted with one to three halo, heterocyclyl, orheteroaryl, wherein the heterocyclyl or heteroaryl is optionallysubstituted with one to three substituents independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo.

In certain embodiments, R⁴² is a fused bicyclic ring system having aheterocyclyl fused to a heteroaryl, wherein the ring system is attachedto the remainder of the molecule via the heterocyclyl. In certainembodiments, R⁴² is a fused bicyclic ring system having a cycloalkylfused to a heteroaryl, wherein the ring system is attached to theremainder of the molecule via the cycloalkyl.

In certain embodiments, R⁴² is a fused bicyclic ring system having aheterocyclyl fused to a heteroaryl selected from the group consistingof:

each of which is optionally substituted with C₁₋₃ alkyl, and wherein thewavy line indicates the point of attachment to the remainder of themolecule. In certain embodiments, C₁₋₃ alkyl is methyl.

In certain embodiments, R⁴² is a fused bicyclic ring system having aheterocyclyl fused to a heteroaryl selected from the group consistingof:

each of which is optionally substituted with one to three substituentsindependently selected from C₁₋₃ alkyl or halo, and wherein the wavyline indicates the point of attachment to the remainder of the molecule.In certain embodiments, C₁₋₃ alkyl is methyl.

In certain embodiments, R⁴² is a fused bicyclic ring system having aheterocyclyl fused to a heteroaryl selected from the group consistingof:

each of which is optionally substituted with one to three substituentsindependently selected from C₁₋₃ alkyl or halo, and wherein the wavyline indicates the point of attachment to the remainder of the molecule.In certain embodiments, C₁₋₃ alkyl is methyl.

In certain embodiments, R⁴² is a fused bicyclic ring system having aheterocyclyl fused to a heteroaryl selected from the group consistingof:

each of which is optionally substituted with one to three C₁₋₃ alkyl,and wherein the wavy line indicates the point of attachment to theremainder of the molecule. In certain embodiments, C₁₋₃ alkyl is methyl.

Also provided is a compound having the formula (D-II):

wherein each X¹ is independently C or N:

each X² is independently CR⁵⁵, N, NR⁵⁵, O, or S,

each R⁵⁵ and R⁵⁶ is independently H, halo, cyano. C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, amino, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆cyanoalkyl, C₁₋₆ aminoalkyl, —S(O)₂(C₁₋₆ alkyl), —C₁₋₆alkylene-S(O)₂(C₁₋₆ alkyl), —C(O)NR⁴⁶R⁴⁷, —NR⁴⁶C(O)R⁴⁷—, —C₁₋₆alkylene-C(O)NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶C(O)R⁴⁷, —SO₂N⁴⁶R⁴⁷,—NR⁴⁶SO₂R⁴⁷, —C₁₋₆ alkylene-SO₂NR⁴⁶R⁴⁷, —C₁₋₆ alkylene-NR⁴⁶SO₂R⁴⁷,—C(O)R⁴⁶, —OC(O)R⁴⁶, —C(O)₂R⁴⁶, —C₁₋₆ alkylene-C(O)R⁴⁶, —C₁₋₆alkylene-OC(O)R⁴⁶, —C₁₋₆ alkylene-C(O)₂R⁴⁶, —O—C(O)NR⁴⁶R⁴⁷,—NR⁴⁶C(O)OR⁴⁷, —C¹⁻⁶ alkylene-O—C(O)NR⁴⁶R⁴⁷, —C₁₋₆alkylene-NR⁴⁶C(O)OR⁴⁷, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;

m is 0 or 1; and

n is 0, 1, 2 or 3.

The remaining variables of formula (D-II) are as defined herein. Alsoprovided is a compound having the formula (D-II) or a pharmaceuticallyacceptable salt, prodrug, stereoisomer, or a mixture of stereoisomersthereof.

In some embodiments, at least one X¹ or X² is a heteroatom.

Also provided is a compound having the formula (D-IIa):

Also provided is a compound having the formula (D-IIb):

In certain embodiments,

is:

In certain embodiments,

is:

In certain embodiments,

is selected from:

In certain embodiments,

In some embodiments, R⁴² is not quinuclindinyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzothiazolidinyl, benzoxazolyl,dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, ortetrahydroisoquinolinyl.

Also provided is a compound having the formula (D-III):

or a pharmaceutically acceptable salt, prodrug, stereoisomer, or amixture of stereoisomers thereof, wherein:

Cy is C₃₋₁₀cycloalkyl:

y is 1, 2, or 3;

each R⁵⁷ is independently selected from amino, C₂₋₆ alkenyl,C₂₋₆alkynyl, cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl), —S(O)₂(C₁₋₆alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy, C₁₋₆hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted with one or more halo,cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,or heteroarylalkyl, wherein the heterocyclyl, heteroaryl orheteroarylalkyl are optionally substituted with one or more substituentsindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo; and

the remaining variables are as defined herein.

In some embodiments, each R¹¹ is independently selected from amino, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyanoalkyl, —S(C₁₋₆ alkyl), —S(O)(C₁₋₆ alkyl),—S(O)₂(C₁₋₆ alkyl), —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₁₋₆ haloalkoxy,C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl substituted with one to three halo,cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,or heteroarylalkyl, wherein the heterocyclyl, heteroaryl orheteroarylalkyl are optionally substituted with one to threesubstituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, orhalo.

Also provided is a compound having the formula (D-IIIa):

Also provided is a om pound having the formula (D-IIIb):

Also provided is a compound having the formula (D-IIIc):

Also provided is a compound having the formula (D-IIId):

Also provided is a compound having the formula (D-IIIe):

Also provided is a compound having the formula (D-IIIf):

In some embodiments, R⁵⁷ is a heteroaryl optionally substituted with oneto three substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, or halo.

In some embodiments, y is 1, and R⁵⁷ is a heteroaryl optionallysubstituted with one to three substituents independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo. In some embodiments, y is 1, andR⁵⁷ is a heteroaryl selected from the group consisting of pyrazolyl,triazolyl, oxazolyl, or thiadiazolyl, each of which is optionallysubstituted with one to three substituents independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo. In some embodiments, y is 1, andR⁵⁷ is a heterocyclyl optionally substituted with one to threesubstituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, orhalo. In some embodiments, R⁵⁷ is a heterocyclyl selected from the groupconsisting piperazinyl or pyrrolidinyl, each of which is optionallysubstituted with one to three substituents independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, or halo.

In some embodiments, Cy is C₃₋₆cycloalkyl. In some embodiments, Cy iscyclobutyl. In some embodiments, Cy is cyclopentyl.

In some embodiments, each R⁵¹ is independently H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ aminoalkyl, —C₁₋₆ alkylene-S(O)₂(C₁₋₆ alkyl), C₃₋₆cycloalkyl optionally substituted with one to three C₁₋₆alkyl,C₃₋₆cycloalkylalkyl optionally substituted with one or three C₁₋₆ alkyl,heterocyclyl optionally substituted with one to three R⁵³, orheterocyclylalkyl optionally substituted with one to three R⁵³; or twoR⁵¹, together with the nitrogen to which they are attached, form athree- to six-membered heterocyclyl optionally substituted with one tothree R⁵³.

In some embodiments, when R⁴⁵ is C₁₋₆ alkyl, C₁₋₆ alkoxy, orheterocyclyl or when R⁵² is C₁₋₆ alkyl, R⁴⁵ or R⁵² is optionallysubstituted with one or more substituents independently selected fromalkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino,aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R^(y))₃, wherein each R^(y) is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In some embodiments, when R⁴⁵ is C₁₋₆ alkyl, C₁₋₆ alkoxy, orheterocyclyl or when R⁵² is C₁₋₆ alkyl, R⁴⁵ or R⁵² is optionallysubstituted with one to three substituents independently selected fromalkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino,aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfnic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R^(y))₃, wherein each R^(y) is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In some embodiments, R⁴⁸ and R⁴⁹, together with the carbon atom to whichthey are attached, form a C₃₋₁₀ cycloalkyl optionally substituted withone or more substituents independently selected from alkyl, alkenyl,alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R^(y))₃, wherein each R^(y) is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In some embodiments, R⁴⁸ and R⁴⁹, together with the carbon atom to whichthey are attached, form a C₃₋₁₀ cycloalkyl optionally substituted withone to three substituents independently selected from alkyl, alkenyl,alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R^(y))₃, wherein each R^(y) is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In some embodiments, when R⁴⁸ and R⁴⁷ are C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, R⁴⁶or R⁴⁷ is optionally substituted with one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio,acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl,carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo,haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone,imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid,sulfonamido, thiol, thioxo, N-oxide, or —Si(R^(y))₃, wherein each R^(y)is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl.

In some embodiments, when R⁴⁶ and R⁴⁷ are C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, R⁴⁶or R⁴⁷ is optionally substituted with one to three substituentsindependently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio,acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl,carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo,haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone,imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid,sulfonamido, thiol, thioxo, N-oxide, or —Si(R^(y))₃, wherein each R^(y)is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl.

In one embodiment, a compound may be selected from those compounds inTable D-1. Also included within the disclosure are pharmaceuticallyacceptable salts, prodrugs, stereoisomers or a mixture of stereoisomersthereof. In certain embodiments, provided are compounds of Table D-1 foruse in the methods described herein.

TABLE D-1 D-1

D-2

D-3

D-4 Second eluting stereoisomer D-5

D-6

D-7

D-8

D-9

D-10

D-11

D-12

D-13

D-14

D-15

D-16

D-17

D-18

D-19

D-20

D-21

D-22

D-23

D-24 Second eluting stereoisomer D-25

D-26

D-27

D-28

D-29

D-30

D-31

D-32

D-33

D-34

D-35

D-36

D-37

D-38

D-39

D-40

D-41

D-42

D-43

D-44

D-45

D-46

D-47

D-48

D-49

D-50

D-51

D-52

D-53

D-54

D-55

D-56

D-57

D-86 Second eluting stereoisomer D-58

D-59

D-60

D-163 Second eluting stereoisomer D-61

D-62

D-105 Second eluting stereoisomer D-63

D-64

D-65

D-122 First eluting stereoisomer D-66

D-67

D-130 Second eluting stereoisomer D-68

D-132 First eluting stereoisomer D-69

D-143 Fourth eluting stereoisomer D-70

D-96 Second eluting stereoisomer D-71

D-72

D-73

D-74

D-102 First eluting stereoisomer D-75

D-76

D-77

D-78

D-151 Second eluting stereoisomer D-79

D-171 First eluting stereoisomer D-80

D-81

D-82

D-174 First eluting stereoisomer D-83

D-84

D-85

D-87

D-88

D-89

D-90

D-107 Second eluting stereoisomer D-91

D-92

D-170 Second eluting stereoisomer D-93

D-94

D-95

D-97

D-98

D-99

D-100

D-101

D-103

D-104

D-106

D-108

D-109

D-110

D-111

D-112

D-175 Second eluting stereoisomer D-113

D-114

D-156 Fourth eluting stereoisomer D-115

D-116

D-117

D-118

D-119

D-120

D-121

D-166 First eluting stereoisomer D-123

D-124

D-125

D-126

D-127

D-142 Second eluting stereoisomer D-128

D-129

D-131

D-133

D-134 Second eluting stereoisomer D-135

D-136

D-137

D-138

D-139

D-140

D-141

D-149 Second eluting stereoisomer D-144

D-145

D-146

D-147

D-148

D-150

D-152

D-172 First eluting stereoisomer D-153

D-154

D-155

D-157

D-157a

D-158

D-159

D-160

D-161

D-162

D-164

D-165

D-167

D-168

D-169

D-173

D-176

D-177

D-178

D-179

D-180

D-181

D-182

D-183

D-184

D-185

D-186

D-187

D-188

D-189 Second eluting stereoisomer D-190

D-191 Second eluting stereoisomer D-192

D-193

D-194

D-195

D-196

D-197

D-198

D-199

D-200 Second eluting stereoisomer D-201

D-202 Second eluting stereoisomer D-203

D-204

D-205

D-206 Second eluting stereoisomer

Representative stereoisomers of various compounds of Table D-1 are shownin Table D-2 below. In one embodiment, a compound may be selected fromthose compounds in Table D-1 or Table D-2. Also included within thedisclosure are pharmaceutically acceptable salts, prodrugs,stereoisomers or a mixture of stereoisomers thereof. In certainembodiments, provided are compounds of Table D-1 or Table D-2 for use inthe methods described herein.

TABLE D-2

Also provided herein is a method of preparing a compound of formula(D-I), comprising coupling a compound of formula (D-a):

wherein X is a leaving group (e.g., halo), with a compound of formula(D-b):

-   -   under conditions to provide the compound of formula (D-I),        wherein each of the variables is as defined herein.

It is understood that any embodiment of the compounds of a formuladescribed herein, including substructures thereof, and any of thespecific substituents set forth herein in the compounds of any of theformulas as set forth above, may be independently combined with otherembodiments and/or substituents of compounds of any of the formulas toform embodiments of the inventions not specifically set forth above. Inaddition, in the event that a list of substituents is listed for anyparticular R group in a particular embodiment and/or claim, it isunderstood that each individual substituent may be deleted from theparticular embodiment and/or claim and that the remaining list ofsubstituents will be considered to be within the scope of the invention.It is understood that in the present description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

3. Pharmaceutical Compositions and Modes of Administration

For the purposes of administration, the compounds of the presentdisclosure may be administered as a raw chemical or may be formulated aspharmaceutical compositions. Pharmaceutical compositions of the presentdisclosure comprise a compound of any formula described herein and apharmaceutically acceptable carrier, diluent or excipient. Accordingly,different embodiments are directed to pharmaceutical compositionscomprising any one or more of the foregoing compounds or apharmaceutically acceptable salt, prodrug or tautomer thereof, and apharmaceutically acceptable carrier, diluent or excipient, are alsoprovided in various embodiments.

The pharmaceutical compositions of the present disclosure may bespecially formulated for administration in solid or liquid form,including those adapted for the following: oral administration, forexample, drenches (aqueous or non-aqueous solutions or suspensions),tablets, e.g., those targeted for buccal, sublingual, and systemicabsorption, boluses, powders, granules, pastes for application to thetongue; parenteral administration, for example, by subcutaneous,intramuscular, intravenous or epidural injection as, for example, asterile solution or suspension, or sustained-release formulation;topical application, for example, as a cream, ointment, or acontrolled-release patch or spray applied to the skin; intravaginally orintrarectally, for example, as a pessary, cream or foam; sublingually;ocularly; transdermally; or nasally, pulmonary and to other mucosalsurfaces.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, or solvent encapsulatingmaterial, involved in carrying or transporting the subject compound fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate, powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides;and other non-toxic compatible substances employed in pharmaceuticalformulations. Examples of such formulations include, but are not limitedto DMSO, 10 mM DMSO, 8% hydroxypropyl-beta-cyclodextrin in PBS,propylene glycol, etc. For example, in a certain embodiment thecompounds of the disclosure can be used as 4 mM solution in 8%hydroxypropyl-beta-cyclodextrin in PBS for parenteral administration.

As set out herein, certain embodiments of the present compounds maycontain a basic functional group, such as amino or methylamino (NCH₃),and are, thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect refers to the relatively non-toxic, inorganic andorganic acid addition salts of compounds of the present disclosure.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the disclosure in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present disclosure may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present disclosure. These salts can likewisebe prepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the purified compoundin its free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically-acceptable metal cation,with ammonia, or with a pharmaceutically-acceptable organic primary,secondary or tertiary amine. Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present disclosure include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient that can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, this amount will range from about 1% to about 99% of activeingredient, preferably from about 5% to about 70%, most preferably fromabout 10% to about 30%.

In certain embodiments, a formulation of the present disclosurecomprises an excipient selected from the group consisting ofcyclodextrins, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present disclosure. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentdisclosure.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present disclosure withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present disclosure withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the disclosure suitable for oral administration may bein the form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent disclosure as an active ingredient. A compound of the presentdisclosure may also be administered as a bolus, electuary or paste.

In solid dosage forms of the disclosure for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically-acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol, glycerol monostearate, and non-ionic surfactants;absorbents, such as kaolin and bentonite clay; lubricants, such a talc,calcium stearate, magnesium stearate, solid polyethylene glycols, sodiumlauryl sulfate, and mixtures thereof; and coloring agents. In the caseof capsules, tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-shelled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made in asuitable machine in which a mixture of the powdered compound ismoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present disclosure, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions that can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of thedisclosure include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the disclosure forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the disclosurewith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present disclosure which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this disclosure include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this disclosure, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisdisclosure, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present disclosure to the body. Dissolvingor dispersing the compound in the proper medium can make such dosageforms. Absorption enhancers can also be used to increase the flux of thecompound across the skin. Either providing a rate controlling membraneor dispersing the compound in a polymer matrix or gel can control therate of such flux. Such transdermal patches may be used to providecontinuous or discontinuous infusion of the compounds described hereinin controlled amounts. Such patches may be constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this disclosure.

Pharmaceutical compositions of this disclosure suitable for parenteraladministration comprise one or more compounds of the disclosure incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers, which may beemployed in the pharmaceutical compositions of the disclosure includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenyl sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions, which are compatible with body tissue.

The compositions that include at least one compound described herein ora pharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof can be formulatedso as to provide quick, sustained or delayed release of the activeingredient after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolutional systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations.

4. Treatment Methods and Uses

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition of as described herein. Thetherapeutically effective amount may vary depending on the subject, anddisease or condition being treated, the weight and age of the subject,the severity of the disease or condition, and the manner ofadministering, which can readily be determined by one of ordinary skillin the art.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. In this context, the compoundsand compositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of acompound of the present disclosure for a given indication, cell type,individual, and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the compounds andcompositions described herein may be suited are described below or willbecome apparent to those skilled in the art. The selected compounds maybe further characterized to examine the safety or tolerance dosage inhuman or non-human subjects. Such properties may be examined usingcommonly known methods to those skilled in the art.

LRRK2 has been associated with the transition from mild cognitiveimpairment to Alzheimer's disease; L-Dopa induced dyskinesia (Hurley etal., Eur. J, Neurosci., Vol. 26, 2007, 171-177); CNS disordersassociated with neuroprogenitor cell proliferation and migration, andregulation of LRRK2 may have utility in improving neurological outcomesfollowing ischemic injury, and stimulating restoration of CNS functionfollowing neuronal injury such as ischemic stroke, traumatic braininjury, or spinal cord injury (Milosevic et al., Neurodegen., Vol. 4,2009, 25; See Zhang et al., J. Neurosci. Res. Vol. 88, 2010, 3275-3281);Parkinson's disease, Alzheimer's disease, multiple sclerosis, andHIV-induced dementia (See Milosevic et al., Mol. Neurodegen., Vol. 4,2009, 25); kidney, breast, prostate (e.g. solid tumor), blood and lungcancer, and acute myeologenouse leukemia (AML); lymphomas and leukemias(See Ray et al., J. Immunolo., Vol. 230, 2011, 109); multiple myeoloma(Chapman et al., Nature. Vol. 471, 2011, 467-472); papillary renal andthyroid carcinomas; multiple myeloma (Chapman et al., Nature, Vol. 471,2011, 467-472); diseases of the immune system, including rheumatoidarthritis, systemic lupus erythematosus autoimmune hemolytic anemia,pure red cell aplasia, idiopathic thrombocytopenic pupura (ITP), Evanssyndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus,Sjogren's syndrome, Delvic's disease, and inflammatory myopathies(Nakamura et al., DNA Res. Vol. 13(4), 2006, 169-183; See Engel et al.,Pharmacol. Rev. Vol. 63, 2011, 127-156; Homam et al., J. Clin.Neuromuscular Disease, Vol. 12, 2010, 91-102); ankylosing spondylitisand leprosy infection (DAnoy et al., PLoS Genetics, Vol. 6(12), 2010,e1001195, 1-5; see Zhang et al., N. Eng. J. Med. Vol. 361, 2009,2609-2618); alpha-synucleinopathies, taupathies (See Li et al., 2010Neurodegen. Dis. Vol. 7, 2010, 265-271); Gaucher disease (See Vestbroeket al., Trends. Mol. Med. Vol. 17, 2011, 485-493); tauopathy diseasescharacterized by hyperphosphorylation of Tau such as argyrophilic graindisease, Pick's disease, corticobasal degeneration, progressivesupranuclear palsy, and inherited frontotemporal dementia andparkinsonism linked to chromosome 17 (See Goedert, M and Jakes, R,Biochemica et Biophysica Acta, Vol. 1739, 2005, 240-250); diseasescharacterized by diminished dopamine levels such as withdrawalsymptoms/relapse associated with drug addiction (See Rothman et al., og.Brain Res., Vol. 172, 2008, 385); microglial proinflammatory responses(See Moehle et al., J. Neuroscience Vol. 32, 2012, 1602-1611); Crohn'sdisease pathogenesis (see Barrett et al., Nature Genetics, Vol. 40,2008, 955-962); and amyotrophic lateral sclerosis (ALS).

It is suggested that increased LRRK2 activity may be characteristic ofALS. Significantly elevated levels of LRRK2 mRNA have been observed infibroblasts of Niemann-Pick Type C (NPC) disease patients, indicatingabnormal LRRK2 function may play a role in lysosomal disorders.

In another aspect, the present disclosure relates to a method oftreating a disease or condition mediated, at least in part, by LRRK2. Inparticular, the disclosure provides methods for preventing or treating adisorder associated with LRRK2 in a mammal, comprising the step ofadministering to said mammal a therapeutically effective amount of acompound of structure (I) or therapeutic preparation of the presentdisclosure. In some embodiments the LRRK-mediated disease or conditionis a neurodegenerative disease, for examples a central nervous system(CNS) disorder, such as Parkinson's disease (PD), Alzheimer's disease(AD), dementia (including Lewy body dementia and cascular dementia),amyotrophic lateral sclerosis (ALS), age related memory dysfunction,mild cognitive impairment (i.e. including the transition from mildcognitive impairment to Alzheimer's disease), argyrophilic graindisease, lysosomal disorders (for example, Niemann-PickType C disease,Gaucher disease) corticobasal degeneration, progressive supranuclearpalsy, inherited frontotemporal dementia and parkinsonism linked tochromosome 17 (FTDP-17), withdrawal symptoms/relapse associated withdrug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD),and HIV-associated dementia (HAD). In other embodiments the disorder isan ischemic disease of organs including but not limited to brain, heart,kidney, and liver.

In some other embodiments, the disease or condition mediated, at leastin part, by LRRK2, is cancer. In certain embodiments, the cancer isthyroid, renal (including papillary renal), breast, lung, blood, andprostate cancers (e.g. solid tumor), leukemias (including acutemyelogenous leukemia (AML)), lymphomas, or leukemias. In someembodiments, the cancer is kidney cancer, breast cancer, prostatecancer, blood cancer, papillary cancer, lung cancer, acute myelogenousleukemia or multiple myeloma.

In other embodiments, the presently disclosed compounds are used inmethods for treatment of inflammatory disorders. In some embodiments,the disorder is an inflammatory disease of the intestines such asCrohn's disease or ulcerative colitis (both generally known together asinflammatory bowel disease). In other embodiments, the inflammatorydisease is leprosy, amyotrophic lateral sclerosis, rheumatoid arthritis,or ankylosing spondylitis. In some embodiments, the inflammatory diseaseis leprosy, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, amyotrophic lateral sclerosis, rheumatoid arthritis orankylosing spondylitis.

In other embodiments, the presently disclosed compounds are used inmethods for treatment of multiple sclerosis, systemic lupuserythematosus, autoimmune hemolytic anemia, pure red cell aplasia,idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis,bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome,Devic's disease and inflammatory myopathics.

Other embodiments include methods for enhancing cognitive memory of asubject, the method comprising administering an effective amount of acomposition comprising the compound of a formula described herein to asubject in need thereof.

The term “trauma” as used herein refers to any physical damage to thebody caused by violence, accident, fracture etc. The term “ischemia”refers to a cardiovascular disorder characterized by a low oxygen stateusually due to the obstruction of the arterial blood supply orinadequate blood flow leading to hypoxia in the tissue. The term“stroke” refers to cardiovascular disorders caused by a blood clot orbleeding in the brain, most commonly caused by an interruption in theflow of blood in the brain as from clot blocking a blood vessel, and incertain embodiments of the disclosure the term stroke refers to ischemicstroke or hemorrhagic stroke. The term “myocardial infarction” refers toa cardiovascular disorder characterized by localized necrosis resultingfrom obstruction of the blood supply.

In certain embodiments, a compound or pharmaceutical composition isadministered orally. In other embodiments, the compound orpharmaceutical composition is administered intravenously. Alternativeroutes of administration include sublingual, intramuscular, andtransdermal administrations.

In certain embodiments, the present disclosure relates to compounds forinhibiting cell death, wherein the compounds are represented by thestructure of any formula described herein. In certain embodiments, thecompounds of the present disclosure are inhibitors of cell death. In anyevent, the compounds of the present disclosure preferably exert theireffect on inhibiting cell death at a concentration less than about 50micromolar, more preferably at a concentration less than about 10micromolar, and most preferably at a concentration less than 1micromolar.

The compounds of the disclosure can be tested in standard animal modelsof stroke and standard protocols such as described by Hara, H., et al.Proc Natl Acad Sci USA, 1997. 94(5): 2007-12.

When the compounds of the present disclosure are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1% to 99.5% (morepreferably, 0.5% to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present disclosure may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracistemally and topically, as by powders, ointments ordrops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent disclosure, which may be used in a suitable hydrated form,and/or the pharmaceutical compositions of the present disclosure, areformulated into pharmaceutically-acceptable dosage forms by conventionalmethods known to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this disclosure may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentdisclosure employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with the particular compound employed, the age, sex, weight,condition, general health and prior medical history of the patient beingtreated, and like factors well known in the medical arts. A daily,weekly, or monthly dosage (or other time interval) can be used.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the disclosure employed in thepharmaceutical composition at levels lower than that required to achievethe desired therapeutic effect and then gradually increasing the dosageuntil the desired effect is achieved.

In general, a suitable daily dose of a compound of the disclosure willbe that amount of the compound that is the lowest dose effective toproduce a therapeutic effect (e.g., inhibit necrosis). Such an effectivedose will generally depend upon the factors described above. Generallydoses of the compounds of this disclosure for a patient, when used forthe indicated effects, will range from about 0.0001 to about 100 mg perkg of body weight per day. Preferably the daily dosage will range from0.001 to 50 mg of compound per kg of body weight, and even morepreferably from 0.01 to 10 mg of compound per kg of body weight.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

In another aspect of the disclosure the compounds can be administered incombination with other agents, including (but not limited to) compoundsthat are apoptosis inhibitors; PARP poly(ADP-ribose) polymeraseinhibitors; Src inhibitors; agents for the treatment of cardiovasculardisorders; anti-inflammatory agents, anti-thrombotic agents;fibrinolytic agents; anti-platelet agents, lipid reducing agents, directthrombin inhibitors; glycoprotein IIb/IIIa receptor inhibitors; calciumchannel blockers; beta-adrenergic receptor blocking agents;cyclooxygenase (e.g., COX-1 and COX-2) inhibitors; angiotensin systeminhibitor (e.g., angiotensin-converting enzyme (ACE) inhibitors); renininhibitors; and/or agents that bind to cellular adhesion molecules andinhibit the ability of white blood cells to attach to such molecules(e.g., polypeptides, polyclonal and monoclonal antibodies).

The disclosure also provides combinations of two or more compounds thatinhibit cellular necrosis (e.g., a compound as disclosed herein and anadditional agent for inhibiting necrosis). The disclosure also providescombinations of one or more compounds that inhibit cellular necrosiscombined with one or more additional agents or compounds (e.g., othertherapeutic compounds for treating a disease, condition, or infection).

5. Kits

The disclosure also provides kits including one or more compounds orcombinations of the disclosure, or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof, and suitable packaging. A kit can also include one ormore additional agents or compounds described herein. The differentcomponents of the kit can be provided in different containers. The kitcan be compartmentalized to receive the containers in close confinement.The kit can also contain instructions for using the compounds accordingto the disclosure.

As used herein, a kit such as a compartmentalized kit includes any kitin which compounds or agents are contained in separate containers.Illustrative examples of such containers include, but are not limitedto, small glass containers, plastic containers or strips of plastic orpaper. Particularly preferred types of containers allow the skilledworker to efficiently transfer reagents from one compartment to anothercompartment such that the samples and reagents are notcross-contaminated and the agents or solutions of each container can beadded in a quantitative fashion from one compartment to another. Suchcontainers include, but are not limited to, a container that will accepta compound or combination of compounds and/or other agents of thedisclosure. One or more compounds or agents can be provided as a powder(e.g. lyophilized powder) or precipitate. Such compound(s) can beresuspended prior to administration in a solution that may be providedas part of the kit or separately available. A kit can contain compoundsor agents in other forms such as liquids, gels, solids, as describedherein. Different compounds and/or agents may be provided in differentforms in a single kit.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof in a suitable container. The container may be a vial, jar,ampoule, preloaded syringe, or intravenous bag.

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the compounds of the present disclosure and methods fortesting such compounds. It is to be understood that the scope of thepresent disclosure is not limited in any way by the scope of thefollowing examples. In the following examples, and throughout thespecification and claims, molecules with a single chiral center (such ascompound (I)), unless otherwise noted, exist as a racemic mixture.Single enantiomers may be obtained by methods known to those skilled inthe art.

The following examples are provided for purposes of illustration, notlimitation. It should be appreciated by those of skill in the art thatthe techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the embodimentswhich are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the disclosure.

6. General Experimental Methods

The compounds of the present invention can be prepared according to anynumber of methods known in the art, including those methods specificallydescribed in the Examples below. The following General Reaction Scheme Iillustrates a method of making compounds of this disclosure, i.e.,compounds of formula (I), wherein R¹, R², R^(3a), R^(3b), R⁴, R⁵ and Zare as defined above, and X and X′ are independently halogens.

Referring to General Reaction Scheme I, compound (a) is purchased fromcommercial sources or prepared according to methods known in the art.Coupling (for example, Buchwald-Hartwig or Suzuki coupling) of (a) withH—R² or an appropriately functionalized derivative thereof (e.g.,boronic acid derivative) yields compound (b). Amination of compound (b)with pyrazole (c) yields desired compound of formula I. Modifications tothe above General Scheme are also possible, for example the coupling andamination steps can be reversed.

It is understood that one skilled in the art may be able to make thesecompounds by similar methods or by combining other methods known to oneskilled in the art. It is also understood that one skilled in the artwould be able to make, in a similar manner as described below, othercompounds of structure (I) not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions. Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this disclosure.

It will also be appreciated by those skilled in the art that in theprocess described herein the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(for example, t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for amino, amidino and guanidino includet-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protectinggroups for mercapto include —C(O)—R″ (where R″ is alkyl, aryl orarylalkyl), p-methoxybenzyl, trityl and the like. Suitable protectinggroups for carboxylic acid include alkyl, aryl or arylalkyl esters.Protecting groups may be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein. The use of protecting groups is described in detail in Green, T.W. and P. G. M Wutz, Protective Groups in Organic Synthesis (1999), 3rdEd., Wiley. As one of skill in the art would appreciate, the protectinggroup may also be a polymer resin such as a Wang resin, Rink resin or a2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this disclosure may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of thedisclosure which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisdisclosure are included within the scope of the disclosure.

Furthermore, all compounds of the disclosure which exist in free base oracid form can be converted to their pharmaceutically acceptable salts bytreatment with the appropriate inorganic or organic base or acid bymethods known to one skilled in the art. Salts of the compounds of thedisclosure can be converted to their free base or acid form by standardtechniques.

Where the preparation of starting materials is not described, these arecommercially available, known in the literature or readily obtainable bythose skilled in the art using standard procedures. Where it is statedthat compounds were prepared analogously to earlier examples orintermediates, it will be appreciated by the skilled person that thereaction time, number of equivalents of reagents and temperature can bemodified for each specific reaction and that it may be necessary ordesirable to employ different work-up or purification techniques.

A: Compound Preparation

In the following examples, all non-aqueous reactions were carried out inoven-dried or flame-dried glassware under nitrogen atmosphere. Allchemicals were purchased from commercial vendors and used as is, unlessotherwise specified. Reactions were magnetically stirred and monitoredby thin layer chromatography (TLC) with 250 μm pre-coated silica gelplates, visualized either with UV, or in an iodine chamber. Flash columnchromatography was performed using silica gel (100-200 mesh). Chemicalshifts are reported relative to chloroform (δ7.26), methanol (δ3.31), orDMSO (δ2.50) for ¹H NMR. HPLC analysis was performed on Shimadzu 20ABHPLC system with a photodiode array detector and Luna-C18(2) 2.0×50 mm,5 μm column at a flow rate of 1.2 mL/min with a gradient solvent Mobilephase A (MPA, H₂O+0.037% (v/v) TFA): Mobile phase B (MPB, ACN+0.018%(v/v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected under 220 and 254 nmor used evaporative light scattering (ELSD) detection as well aspositive electrospray ionization (MS). Semi-preparative HPLC wasperformed by either acidic or neutral condition. Acidic: Luna C18 100×30mm, 5 μm; MPA: HCl/H₂O=0.04%, or formic acid/H₂O=0.2% (v/v); MPB: ACN.Neutral: Waters Xbridge 150×25, 5 μm; MPA: 10 mM NH₄HCO, in H₂O; MPB:ACN. Gradient for both conditions: 10% of MPB to 80% of MPB within 12min at a flow rate of 20 mL/min, then 100% MPB over 2 min, 10% MPB over2 min, UV detector.

Example A-1 Synthesis of2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (A-1) Methyl2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate

To a solution of 3-methyl-4-nitro-1H-pyrazole (40 g, 314.71 mmol) in DMF(700 mL) was added NaH (18.88 g, 472.06 mmol, 60% purity) at 0° C. overa period of 30 min under N₂. The reaction was then stirred at 25° C. for2 h followed by the addition of methyl 2-bromo-2-methylpropanoate (85.46g, 472.06 mmol, 61.04 mL) dropwise at 0° C. The reaction mixture waswarmed to 25° C. and stirred at 25° C. for another 16 h. TLC (petroleumether/ethyl acetate=5:1) showed the starting material was consumedcompletely. The reaction was quenched by ice water slowly and thenextracted with EtOAc (3×700 mL). The combined organic phase was washedwith brine (3×200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (petroleum ether/ethyl acetate=30:1-15:1), to yield thedesired product as a light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.29(s, 1H), 3.72 (s, 1H), 2.51 (s, 1H), 1.84 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid

To a mixture of methyl2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g, 306.75mmol) in THF (1 L) and H₂O (250 mL) was added LiOH H₂O (15.45 g, 368.10mmol) at 25° C. under N₂. The mixture was then stirred at 25° C. for 16h. TLC (petroleum ether/ethyl acetate=5:1) showed the reaction wascompleted. The reaction mixture was concentrated in vacuo. The residualaqueous solution was washed with ethyl acetate (50 mL). The aqueousphase was then cooled to 0° C., adjusted to approximately pH 1-2, andfiltered to yield the desired product as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 8.65 (s, 1H), 2.48 (s, 1H), 1.83 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide

To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoicacid (25 g, 117.27 mmol) in DCM (500 mL) was added 8 drops of DMF,followed by oxalyl dichloride (29.77 g, 234.54 mmol) at 0° C. under N₂.Then the mixture was stirred at 25° C. for a further 2 h. TLC (petroleumether/ethyl acetate=3:1) showed reaction was completed. The reactionsolution was concentrated in vacuo. The residue solid was dissolved inTHF (300 mL) and added dropwise into a stirred solution of NH₄OH (413.61g, 11.80 mol, 454.52 mL) at 0° C. The reaction was stirred at 25° C. for1 h. TLC (ethyl acetate) showed reaction was completed. The solution wasthen concentrated in vacuo and partitioned between EtOAc (100 mL) andwater (100 mL), and the aqueous phase was extracted with ethyl acetate(3×80 mL). The combined organic phase was washed with brine (3×40 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo, toyield the desired compound as a yellow solid. ¹H NMR (400 MHz, MeOD): δ8.81 (s, 1H), 7.16-7.26 (m, 2H), 2.42 (s, 3H), 1.71 (s, 3H).

2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile

A solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22g, 103.67 mmol) in POCl₃ (132 g, 860.89 mmol, 80 mL) was stirred at 90°C. for 1 h. TLC showed the reaction was completed. The mixture wascooled to 20° C. and concentrated in vacuo at 50° C. The residue waspoured into ice-water (w/w=1/1) (200 mL) and stirred for 10 min. Theaqueous phase was adjusted to pH=7 with NaHCO₃ solution, extracted withethyl acetate (4×80 mL). The combined organic phase was washed withbrine (40 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo. The desired product was afforded as a yellow solid.

2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile

To a mixture of2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g, 51.5mmol) in EtOH (240 mL) and H₂O (60 mL) was added NH₄Cl (13.77 g, 257.5mmol) in one portion at 25° C., followed by Fe (14.38 g, 257.5 mmol).The mixture was heated to 80° C. and stirred for 1 h. TLC showed thereaction was completed. The solution was cooled to 20° C. The mixturewas extracted with ethyl acetate (3×100 mL), the combined organic layerswere washed with NaHCO₃ solution (50 mL) and brine (50 mL). The organiclayers were dried over Na₂SO₄, filtered and concentrated. The desiredproduct was afforded as a dark brown solid. ¹H NMR (400 MHz, CDCl₃): δ7.17 (s, 1H), 2.18 (s, 3H), 1.91 (s, 6H).

2-[4-[(5-trifluoromethyl-4-chloro-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

A mixture of 2,4-dichloro-5-(trifluoromethyl) pyrimidine (2.00 g, 9.22mmol), 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (1.51g, 9.22 mmol), NaHCO₃ (2.32 g, 27.66 mmol, 1.08 mL) in acetonitrile (20mL) was stirred at 25° C. for 3 h under N₂ atmosphere. LC-MS showedcomplete reaction of starting material. Two new peaks were shown inLC-MS and 85% of desired compound was detected. The reaction mixture wasfiltered and the filtrate was concentrated in vacuo to afford the crudedesired product as a brown oil. The crude product was often used in thenext synthetic step without further purification. A portion of the crudeproduct was purified by prep-HPLC the pure desired product was affordedas a white solid. ¹H NMR (CDCl3 400 MHz): δ 8.48-8.68 (m, 1H), 8.15 (s,1H), 6.97 (bs, 1H), 2.29 (s, 3H), 2.01 (s, 6H).

2-[4-[(5-trifluoromethyl-4-cyclopropyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-1)

A mixture of2-[4-[(5-trifluoromethyl-4-chloro-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(100.00 mg, 290.09 μmol, 1.00 eq), cyclopropylboronic acid (124.59 mg,1.45 mmol), Pd(OAc)₂ (6.51 mg, 29.01 μmol, 0.10 eq), PCy₃ (16.27 mg,58.02 μmol, 18.70 μL) and CsF (132.19 mg, 870.27 μmol, 32.09 μL) indioxane (5.00 mL) was de-gassed under N₂ and then heated to 90° C. for12 hours under N₂. LC-MS was used to monitor reaction progress. Thereaction mixture was diluted with H₂O (20 mL) and extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine (5mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=10:1-3:1) followed by prep-HPLC (neutralcondition) to provide the title compound. ¹H NMR (CDCl₃ 400 MHz): δ 8.45(s, 1H), 8.12 (s, 1H) 6.73 (bs, 1H), 2.20-2.34 (m, 4H), 2.00 (s, 6H),1.26-1.35 (m, 2H), 1.11-1.23 (m, 2H). HPLC: RT 3.1 min. MS: m/z: 351.2[M+H]⁺.

Example A-2 Synthesis of2-[4-[(5-chloro-4-cyclopropyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-2) 2,5-dichloro-4-cyclopropyl-pyrimidine

A mixture of 2,4,5-trichloropyrimidine (750 mg, 4.09 mmol),cyclopropylboronic acid (1.76 g, 20.45 mmol), CsF (1.86 g, 12.27 mmol),Pd(OAc)₂ (91 mg, 409 uμmol) and PCy₃ (114 mg, 409 μmol) in 1,4-dioxane(20 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 90° C. for 16 h under N₂ atmosphere. The solutionwas concentrated in vacuo. To the residue was added water (20 mL),extracted with ethyl acetate (3×15 mL). The organic layers werecombined, washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give a crude product. The crude product was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=100%petroleum ether-10:1) to afford the crude desired compound. ¹H NMR (400MHz, CDCl₃): δ8.38 (s, 1H), 3.72 (s, 1H), 2.44˜2.49 (m, 1H), 1.23˜1.32(m, 4H). LC/MS: RT 0.833 min, m/z=188.9, 190.9 [M+H]⁺.

2-[4-[(5-chloro-4-cyclopropyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-2)

To a solution of 2,5-dichloro-4-cyclopropyl-pyrimidine (230 mg, 547.50μmol) and 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(prepared as described in the examples above; 404 mg, 2.46 mmol) in1,4-dioxane (10 mL) was added p-TsOH (9 mg, 54.75 μmol). The mixture wasstirred at 100° C. for 16 h. The mixture was concentrated in vacuo. Tothe residue was added water (10 mL), adjusted to pH=7 with NaHCO₃solution, extracted with ethyl acetate (3×10 mL). The organic layerswere combined, washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by prep-HPLC(neutral condition) and lyophilized to provide the title compound. ¹HNMR (400 MHz, CDCl3): δ8.19 (s, 1H), 8.10 (s, 1H), 6.44 (br, 1H),2.41˜2.47 (m, 1H), 2.27 (s, 3H), 2.00 (s, 6H), 1.20˜1.21 (m, 2H),1.14˜1.16 (m, 2H). HPLC: RT 3.34 min. MS: (M+H+) m/z: 317.1.

Example A-3 Synthesis of2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-pyrimidine-5-carbonitrile(A-3)4-chloro-2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]pyrimidine-5-carbonitrile

To a solution of 2,4-dichloropyrimidine-5-carbonitrile (530 mg, 3.05mmol) in CH₃CN (10 mL) was added NaHCO₃ (768 mg, 9.15 mmol) and2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (500 mg,3.05 mmol) at 25° C. The mixture was stirred at 25° C. for 16 h. Thesolution was concentrated in vacuo to give a residue. To the residue wasadded water (20 mL), extracted with ethyl acetate (3×15 mL). The organiclayers were combined, washed with brine (10 mL), dried over Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to give a crudeproduct. The crude product was purified by prep-HPLC (neutralcondition). The eluent was extracted with ethyl acetate (3×20 mL),washed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedin vacuo to afford the desired crude product as a brown solid. ¹H NMR(400 MHz, CDCl₃): δ8.51˜8.61 (m, 1H), 8.13 (s, 1H), 7.08˜7.15 (m, 1H),2.28˜2.30 (m, 3H), 2.01 (s, 6H). LC/MS: RT 0.750 min, m/z=302.0 [M+H]⁺.

2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-pyrimidine-5-carbonitrile(A-3)

A mixture of4-chloro-2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]pyrimidine-5-carbonitrile(140 mg, 463.99 μmol), cyclopropylboronic acid (199 mg, 2.32 mmol),K₃PO₄ (295 mg, 1.39 mmol), Pd(dppf)Cl₂ (34 mg, 46.40 μmol) and Ag₂O (11mg, 46.40 μmol) in 1,4-dioxane (1 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 80° C. for 16 h underN₂. The solution was concentrated in vacuo to give a residue. To theresidue was added water (10 mL), extracted with ethyl acetate (3×10 mL).The organic layers were combined, washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by prep-HPLC (neutral condition) and lyophilized to afford thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 8.43˜8.50 (m, 1H), 8.10 (s,1H), 6.73˜6.94 (m, 1H), 2.37 (m, 1H), 2.28 (s, 3H), 1.99 (s, 6H), 1.30(m, 4H). HPLC: RT 80 min. MS: m/z: 308.2 [M+H]⁺.

Example A-4 Synthesis of2-[4-[[4-(cyclopenten-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-4); and2-[4-[[4-cyclopentyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-10)2-[4-[[4-(cyclopenten-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-4)

2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrilewas prepared according to the procedures described above. A mixture of2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(300 mg, 870.27 μmol), cyclopenten-1-ylboronic acid (584 mg, 5.22 mmol),Cs₂CO₃ (850 mg, 2.61 mmol) and Pd(dppf)Cl₂ (63 mg, 87.03 μmol) in1,4-dioxane (3 mL), acetonitrile (3 mL) and H₂O (1 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 90° C.for 16 h under N₂. The reaction mixture was concentrated in vacuo toremove solvent. The residue was purified by prep-TLC (SiO₂, petroleumether/ethyl acetate=4:1) to afford title compound. ¹H NMR (400 MHz,CDCl₃): δ8.61 (s, 1H), 8.24 (s, 1H), 6.88 (s, 1H), 2.86 (s, 2H), 2.62(s, 2H), 2.29 (s, 1H), 2.02-2.07 (m, 2H), 2.00 (s, 6H). HPLC: RT 3.69min. MS: m/z: 399.1 [M+Na]⁺

2-[4-[[4-cyclopentyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-10)

To a solution of2-[4-[[4-(cyclopenten-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(200 mg, 0.53 mmol) in EtOAc (20 mL) was added Pd/C (10%, 0.1 g) underN₂. The suspension was degassed and purged with H₂ for 3 times. Themixture was stirred under H₂ (15 psi) at 25° C. for 3 h. The reactionsolution was filtered through a pad of celite. The filtrate wasconcentrated in vacuo to give a crude product. The crude product waspurified by prep-HPLC (neutral condition) and lyophilized to affordtitle compound. ¹H NMR (400 MHz, CDCl³): δ 8.51 (s, 1H), 8.25 (s, 1H),6.80 (s, 1H), 3.40 (m, 1H), 2.31 (s, 3H), 2.00˜2.04 (m, 8H), 1.91 (m,4H), 1.73 (m, 2H). HPLC: RT 3.06 min. NIS: m/z: 379.2 [M+H]⁺

Example A-5 Synthesis of2-(5-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile(A-5) 2,2-dimethyl-3-oxopentanedinitrile

A stirred suspension of NaH (1.3 g, 31.88 mmol, 60% purity) in THF (25mL) was heated to 75° C. To this was added a mixture of2,2-dimethyl-2-cyanoacetic acid ethyl ester (3 g, 21.25 mmol) and CH₃CN(1.7 mL, 31.88 mmol) in THF (20 mL) dropwise over a period of 45 min.The resulting pale yellow suspension was heated at 70° C. for a further15 h. The reaction mixture was poured into water (150 mL) and theresulting solution was extracted with EtOAc (2×100 mL). The aqueouslayer was separated, acidified to pH 2 with aqueous 1 M HCl, andextracted with EtOAc (2×100 mL). The combined organic layers were driedover Na₂SO₄ and then concentrated under reduced pressure to afford2,2-dimethyl-3-oxopentanedinitrile as yellow oil. LCMS: RT 0.213 min,m/z=137.1 [M+H]⁺.

2-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile

A mixture of 2,2-dimethyl-3-oxopentanedinitrile (5-2)(500 mg, 3.67 mmol)and methylhydrazine (0.2 mL, 3.67 mmol) in EtOH (20 mL) was treated withcone HCl (0.4 mL, 11 mmol) in at 25° C. The mixture was stirred at 90°C. for 12 h. The mixture was poured into ice-water (20 mL) and extractedwith EtOAc (20 mL×3). The combined organic phase was concentrated underreduced pressure to give a residue. The residue was purified on a shortsilica gel plug eluting with DCM to DCM:MeOH (10:1) to give2-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile as a yellowoil. LCMS: RT 0.456 min, m/z=165.2 [M+H]⁺.

2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (300 mg,1.38 mmol) in CH₃CN (9 mL) and H₂O (9 mL) was added cyclopropanecarboxylic acid (357 mg, 4.14 mmol), (NH₄)₂S₂O₈ (1.57 g, 6.90 mmol) andAgNO₃ (940 mg, 5.52 mmol) at 25° C. The reaction mixture was warmed to60° C. and stirred for 6 h under N₂. The reaction was quenched by icewater and then extracted with EtOAc (20 mL×3). The combined organicphase was washed with brine (20 mL×3), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (PE:EtOAc=20:1), to give2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine as a colorless oil.¹H NMR (400 MHz, CDCl₃): δ 8.57 (s, 1H), 2.17-2.26 (m, 1H), 1.31-1.40(m, 2H), 1.16-1.25 (m, 3H).

2-(5-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile(A-5)

To a solution of2-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (100 mg, 0.6mmol) in n-BuOH (1 mL) was added2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (136 mg, 0.6 mmol)and a drop of trifluoroacetic acid (5.00 μL) at 25° C. The solution wasstirred at 100° C. for 1.5 h under microwave irradiation. The mixturewas concentrated under reduced pressure to give a residue. The residuewas purified by prep-HPLC (column: Luna C8 100*30 5 u; liquid phase:[A-10 mM NH₄HCO₃ in H₂O; B-ACN] B %: 35%-60%, 12 min]) to give2-(5-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile.¹H NMR: (400 MHz, DMSO): δ 8.57 (s, 1H), 7.26 (br. s., 1H), 6.26 (s,1H), 3.62 (s, 3H), 2.06-2.16 (m, 1H), 1.60 (s, 6H), 1.12 (d, J=6.4 Hz,4H). HPLC: RT 3.34 min. MS: m/z: 351.1 [M+H]⁺.

Example A-6 Synthesis of2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-cyclopentylpyrimidine-5-carbonitrile(A-6)

This compound can be synthesized using a method analogous to Example A-4or Example A-10.

Example A-7 Synthesis of4-cyclopropyl-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-7) 3-methyl-1-methylsulfonyl-4-nitro-pyrazole

To a mixture of 3-methyl-4-nitro-1H-pyrazole (1 g, 7.87 mmol) andtriethylamine (1.59 g, 15.74 mmol) in DCM (50 mL) was added MsCl (1.35g, 11.81 mmol) dropwise at 0° C. Then the mixture was stirred at 25° C.for 12 h. The mixture was poured into aq. sat. NH₄Cl (10 mL). Theaqueous phase was extracted with ethyl acetate (4×20 mL). The combinedorganic phase was washed with brine (4×20 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=3:1) toafford the desired compound as a white solid. ¹H NMR (400 MHz, CDCl₃):δ8.760 (s, 1H), 3.468 (s, 3H) 2.651 (s, 3H). LC/MS: RT 0.569 min,m/z=206 [M+H]⁺.

3-methyl-1-methylsulfonyl-pyrazol-4-amine

To a solution of 3-methyl-1-methylsulfonyl-4-nitro-pyrazole (600 mg,2.92 mmol) in ethanol (10 mL) and water (5 mL) was added Fe (817 mg,14.62 mmol) and NH₄Cl (782 mg, 14.62 mmol). The reaction was stirred at80° C. for 2 h. The reaction mixture was filtered and the filtrate wasconcentrated. The mixture was added with water (10 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic phase was washed withbrine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the desired product. LC/MS: RT 0.094 min, m/z=176[M+H]⁺.

4-chloro-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of 3-methyl-1-methylsulfonyl-pyrazol-4-amine (346 mg, 1.97mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (427 mg, 1.97 mmol)in acetonitrile (10 mL) was added NaHCO₃ (418 mg, 3.94 mmol) in oneportion at 25° C. The mixture was stirred at 25° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by prep-HPLC (TFA acidic) to afford thedesired product as a white solid. ¹H NMR (400 MHz, CDCl₃): δ8.672 (s,1H), 8.577 (s, 1H) 7.112 (s, 1H) 3.331 (s, 1H) 2.398 (s, 1H). LC/MS: RT0.830 min, m/z=356 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-7)

To a mixture of4-chloro-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (250 mg, 702.80 μmol) and cyclopropylboronic acid (362mg, 4.22 mmol) in 1,4-dioxane (5 mL) was added CsF (320 mg, 2.11 mmol),Pd(OAc)₂ (15.8 mg, 70.28 μmol) and PCy₃ (19.7 mg, 70.28 μmol) in oneportion at 25° C. under N₂. The mixture was stirred at 90° C. for 12 h.The mixture was cooled to 25° C. and concentrated in vacuo at 35° C. Theresidue was poured into water (10 mL). The aqueous phase was extractedwith ethyl acetate (3×20 mL). The combined organic phase was washed withbrine (3×20 mL), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by prep-HPLC to afford titlecompound. ¹H NMR (400 MHz, CDCl₃): δ8.524 (s, 2H), 6.757 (s, 1H), 3.300(s, 3H) 2.400 (s, 3H) 2.290 (s, 1H) 1.333 (s, 2H) 1.229 (s, 2H). HPLC:RT 3.36 min. MS: m/z: 362.1[M+H]⁺

Example A-8 Synthesis of4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-8)(E)-N-((dimethylamino)methylene)-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide

2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide used asstarting material for this reaction was prepared according to theprocedure described in the above examples. A mixture of2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (5 g, 23.56mmol) and DMF-DMA (28.07 g, 235.60 mmol) was stirred at 95° C. for 2 h.The mixture was concentrated in vacuo to give afford the crude desiredproduct as a brown oil. The crude product was used in the next syntheticstep without further purification. LC/MS: RT 0.655 min, m/z=268 [M+H]⁺.

3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole

To a solution of(E)-N-((dimethylamino)methylene)-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide(6.6 g, 24.69 mmol) in acetic acid (50 mL) was added NH₂—H₂O (18.92 g,370.35 mmol, 18.37 mL, 98% purity). The mixture was stirred at 95° C.for 1.5 h. The reaction mixture was adjusted by addition of sat. NaHCO₃(200 mL) at 0° C. to pH=9, and then extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to afford the crudedesired product as a brown solid. The crude product was used in the nextsynthetic step without further purification. LC/MS: RT 0.581 min,m/z=237 [M+H]⁺.

1-methyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole

To a solution of3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole (6g, 25.40 mmol) in acetonitrile (30 mL) was added methyl iodide (4.33 g,30.48 mmol) and then Cs₂CO₃ (8.28 g, 25.40 mmol). The mixture wasstirred at 50° C. for 12 h. The reaction mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography on silica gel (petroleum ether/ethyl acetate=5:1-100%ethyl acetate) to afford the desired product as a yellow oil. ¹H NMR(400 MHz, CDCl3): δ ppm 8.18-8.21 (m, 1H) 7.98-8.01 (m, 1H) 3.92 (s, 3H)2.53 (s, 3H) 2.03 (s, 6H). LC/MS: RT 0.638 min, m/z=251 [M+H]⁺.

3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine

To a solution of1-methyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole(2.8 g, 11.19 mmol) in ethanol (50 mL) was added Pd—C (10%, 0.95 g)under N₂. The suspension was degassed in vacuo and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 50° C. for 2h. The reaction mixture was filtered and the filtrate was concentratedin vacuo to afford the crude desired product as a brown solid. The crudeproduct was used in the next synthetic step without furtherpurification. ¹H NMR (400 MHz, CDCl3): δ 7.90-7.94 (m, 1H) 7.13 (s, 1H)3.88 (s, 3H) 2.17 (s, 3H) 1.97 (s, 6H).

4-chloro-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine(400 mg, 1.82 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (394.9mg, 1.82 mmol) and NaHCO₃ (458.69 mg, 5.46 mmol) in CH₃CN (4 mL) wasstirred at 25° C. for 3 h under N₂. The reaction mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified byprep-HPLC (neutral condition) to afford the desired compound as anoff-white solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.39-8.62 (m, 1H)7.89-8.10 (m, 2H) 6.87-7.09 (m, 1H) 3.90 (s, 3H) 2.23 (s, 3H) 2.05 (s,6H). LC/MS: RT 0.785 min, m/z=401 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-8)

A mixture of4-chloro-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(100 mg, 249.51 μmol), cyclopropylboronic acid (107.16 mg, 1.25 mmol),Pd(OAc)₂ (5.6 mg, 24.95 μmol), PCy₃ (13.99 mg, 49.90 μmol) and CsF(113.7 mg, 748.53 μmol) in dioxane (2 mL) was stirred at 90° C. for 12 hunder N₂. The mixture was filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (petroleumether/ethyl acetate=10:1-100% ethyl acetate), and further purified byprep-HPLC (neutral condition) to provide title compound. ¹H NMR (400MHz, CDCl3): δ 8.32-8.44 (m, 1H) 7.81-8.02 (m, 2H) 6.59-6.86 (m, 1H)3.91 (s, 3H) 2.24 (m, 4H) 2.04 (s, 6H) 1.17-1.29 (m, 2H) 1.03-1.14 (m,2H). LC/MS: RT 2.707 min. MS: m/z: 407.2 [M+H]⁺

Example A-9 Synthesis of2-methyl-2-(3-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile(A-9)2-methyl-2-(3-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile(A-9)

2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrilewas prepared according to the procedure described in the above examples.To a solution of2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(150 mg, 0.4 mmol) in dioxane (8 mL) and water (2 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(109 mg, 0.5 mmol) and K₂CO₃ (180 mg, 1.3 mmol) at 25° C. The solutionwas degassed with nitrogen for 5 min followed by addition of Pd(dppf)Cl₂(32 mg, 0.04 mmol) under N₂. The mixture was stirred at 90° C. for 12 h.The mixture was concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (neutral condition) to provide the title compound.¹H NMR (400 MHz, DMSO): δ 9.36-9.71 (m, 1H), 8.66 (s, 1H), 8.21 (s, 1H),7.91 (br. s., 1H), 3.91 (s, 3H), 2.18 (br. s., 3H), 1.94 (s, 6H). HPLC:RT 2.92 min. MS: m/z: 391.1 [M+H]⁺.

Example A-10 Synthesis of2-[4-[[4-cyclobutyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-11)2-[4-[[4-cyclobutyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(A-11)

To a solution of 2,5-dichloro-4-cyclobutylpyrimidine (200 mg, 845.24μmol) and 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(139 mg, 845.24 μmol) in 1,4-dioxane (5 mL) was added p-TsOH (87 mg,507.14 μmol). The mixture was stirred at 100° C. for 12 h. To thesolution was added aq. sat. NaHCO₃ solution (15 mL), stirred for 10 min,the aqueous phase was extracted with EtOAc (3×10 mL). The organic layerswere combined, washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byprep-HPLC (neutral condition) to give2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile.¹H NMR (400 MHz, CDCl₃): δ 8.06-8.59 (m, 2H), 6.90 (br. s., 1H), 3.88(s., 1H), 2.46-2.58 (m, 2H), 2.24-2.40 (m, 5H), 1.91-2.18 (m, 8H). HPLC:RT 3.76 min. MS: (M+H⁺) m/z: 365.1.

Example A-11 Synthesis of2-(4-((4-2-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-12 and A-13)4-(2-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine

To a solution of 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (500mg, 2.21 mmol) in CH₃CN (15 mL) and H₂O (15 mL) was added2-fluorocyclopropanecarboxylic acid (207 mg, 2.0 mmol), (NH₄)₂S₂O₈ (2.5g, 11 mmol) and AgNO₃ (1.5 g, 8.8 mmol). Then the mixture was stirred at25° C. for 12 h. The resulting mixture was extracted with EtOAc (3×15mL). The combined organic extracts were concentrated under reducedpressure to give residue. The residue was purified by prep-TLC(PE:EtOAc=1:1) to give4-(2-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidineas a white solid. LCMS: RT 0.787 min, m/z=285.1 [M+H]⁺.

2-(4-((4-(2-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-12 and A-13)

To a solution of4-(2-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine(50 mg, 0.176 mmol) in dioxane (1 mL) was added2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (35 mg,0.221 mmol) and p-TsOH (9.1 mg, 0.05 mmol) under N₂. Then the mixturewas stirred at 100° C. for 1 h. The mixture was concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC (neutral condition) to give the crude material, which wasfurther purified by chiral SFC to give two peaks of2-(4-((4-(2-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile;peak 1 and peak 2.

Peak 1: ¹H NMR (400 MHz, CHLOROFORM-d): δ 8.49 (br. s., 1H), 8.06 (br.s., 1H), 4.88-5.08 (m, 1H), 2.68 (br. s., 1H) 2.28 (s, 3H), 1.99 (s,6H), 1.58-1.60 (m, 2H). HPLC: RT 2.958 min. MS: (M+H⁺) m/z: 369.2.

Peak 2: ¹H NMR (400 MHz, CHLOROFORM-d): δ 8.49 (br. s., 1H), 8.06 (br.s., 1H), 4.87-5.07 (m, 1H), 2.70 (br. s., 1H), 2.27 (s, 3H), 1.99 (s,6H) 1.62 (d, J=6.2 Hz, 2H). HPLC: RT 2.956 min. MS: (M+H⁺) m/z: 369.2.

Example A-12 Synthesis of 4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-14 and A-15) 3-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole

To a solution of PPh₃ (20.64 g, 78.68 mmol) in THF (30 mL) was addedDIAD (15.91 g, 78.68 mmol, 15.30 mL), 3-methyl-4-nitro-1H-pyrazole (5 g,39.34 mmol) and oxetan-3-ol (2.91 g, 39.34 mmol) at 0° C. Then themixture was stirred at 25° C. for 12 h. The mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (SiO₂, PE:EtOAc=50:1 to 5:1). The mixture of3-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole was obtained as a yellow solid.

3-methyl-1-(oxetan-3-yl)pyrazol-4-amine and5-methyl-1-(oxetan-3-yl)-pyrazol-4-amine

To a solution of Pd/C (3 g, 10% purity) in MeOH (10 mL) was added3-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole (5 g, 37.3 mmol), then themixture was stirred at 25° C. under H₂ (15 psi) for 2 h. The reactionwas filtered and the filtrate was concentrated under reduced pressure togive 3-methyl-1-(oxetan-3-yl)pyrazol-4-amine and5-methyl-1-(oxetan-3-yl)-pyrazol-4-amine as a dark brown oil.

4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-14 and A-15)

2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (300 mg, 1.35mmol), 3-methyl-1-(oxetan-3-yl)pyrazol-4-amine,5-methyl-1-(oxetan-3-yl)-pyrazol-4-amine (271 mg, 1.77 mmol) and TEA(273 mg, 2.7 mmol, 374.26 μL) were taken up into a microwave tube inn-BuOH (8 mL). The sealed tube was heated at 120° C. for 90 min undermicrowave. After cooling to 25° C., the mixture was concentrated underreduced pressure. The residue was purified by prep-TLC (SiO₂,PE:EtOAc=3:1 to 1:1) to provide4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-14 and A-15).

4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-14)

¹H NMR (400 MHz, CDCl₃): δ 8.45 (s, 1H), 8.01 (br. s., 1H), 6.68 (br.s., 1H), 5.38 (quin, J=6.93 Hz, 1H), 5.06 (d, J=6.65 Hz, 4H), 2.29 (s,3H), 2.25 (br. s., 1H), 1.60 (s, 2H), 1.24-1.33 (m, 2H), 1.15 (br. s.,2H). HPLC: RT 2.97 min MS: (M+H⁺) m/z=340.1.

4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-15)

¹H NMR (400 MHz, CDCl₃): δ 8.39 (s, 1H), 7.75 (br. s., 1H), 6.50 (br.s., 1H), 5.41 (quin, J=7.06 Hz, 1H), 5.24 (t, J=6.40 Hz, 2H), 4.94-5.05(m, 2H), 2.13-2.24 (m, 4H), 1.24 (br. s., 2H), 1.10 (dd, J=7.50, 3.09Hz, 2H). HPLC: RT 2.93 min. MS: (M+H) m/z=340.1.

Example A-13 Synthesis of4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-16)3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1-(trideuteriomethyl)-1,2,4-triazole

To a solution of3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole (1g, 4.23 mmol) in CH₃CN (15 mL) was added Cs₂CO₃ (1.38 g, 4.23 mmol) andtridcuterio(iodo)methane (720 mg, 5.08 mmol, 309 μL). The mixture wasstirred at 50° C. for 12 h. The reaction mixture was filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=5:1 to 0:1) to give3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1-(trideuteriomethyl)-1,2,4-triazoleas an off-white solid. LCMS: RT 0.633 min, m/z=254 [M+H]⁺.

3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]pyrazol-4-amine

To a solution of3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1-(trideuteriomethyl)-1,2,4-triazole(300 mg, 1.18 mmol) in EtOH (10 mL) was added Pd—C (10%, 0.125 g) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 50° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to give3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]pyrazol-4-amineas a brown solid. The crude product was used into the next step withoutfurther purification. LCMS: RT 0.225 min, m/z=224 [M+H]⁺.

4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-16)

To a solution of4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (346 mg,1.30 mmol) and3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]pyrazol-4-amine(290 mg, 1.30 mmol) in 1,4-dioxane (10 mL) was added p-TsOH (67 mg,390.00 μmol). The mixture was stirred at 100° C. for 2 h. The reactionmixture was diluted with H₂O (50 mL) and extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (neutral condition) to give title compound4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-16). ¹H NMR: (400 MHz, CHLOROFORM-d): δ 8.30-8.56 (m, 1H), 7.79-8.14(m, 2H), 6.52-6.93 (m, 1H), 2.14-2.30 (m, 4H), 2.04 (s, 6H), 1.18-1.26(m, 2H), 1.04-1.14 (m, 2H). HPLC: RT 2.429 min. MS: (M+H⁺) m/z: 410.2.

Example A-14 Synthesis of2-(3-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-17) 3-chloro-1H-pyrazol-4-amine hydrochloride

Into a 2 L three-necked round-bottom flask affixed with an overheadstirrer, a temperature probe, an addition funnel and a nitrogen inletwere added ethanol (500 mL) and 4-nitro-1H-pyrazole (40 g, 354 mmol). Tothis solution was added, in one portion, conc. HCl (290 mL) (note: rapidexotherm observed from 15° C. to 39° C.) and the resulting mixture waspurged with nitrogen for 5 minutes. Palladium on alumina (5% w/w) (2.1g) was added to the mixture and stirred at room temperature whiletriethylsilane (208 g, 1789 mmol) was added dropwise over 2 h. Thereaction, which started to slowly exotherm from 35° C. to 45° C. over 1h, was stirred for a total of 16 h and vacuum filtered through a plug ofcelite to give a biphasic mixture. The mixture was transferred to aseparatory funnel. The bottom aqueous layer was collected and rotaryevaporated to dryness with the aid of acetonitrile (3×100 mL). Theresulting yellow solid was suspended in acetonitrile (100 mL) andallowed to stand for 0.5 h at room temperature followed by 1 h at 0° C.The solids were filtered and washed with acetonitrile (50 mL) to afford3-chloro-1H-pyrazol-4-amine hydrochloride as a white solid, which wasused to next step without purification. LCMS: RT 0.1 min, m/z=118[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 10.49 (br. s, 2H), 8.02 (s, 0.59H),7.74 (s, 0.31H), 5.12 (br. s, 1H).

tert-butyl (3-chloro-1H-pyrazo4-yl) carbamate

Into a 2 L round bottom flask was added 3-chloro-1H-pyrazo4-aminehydrochloride (30 g, 195 mmol) and THF (150 mL). To this mixture wereadded di-tert-butyldicarbonate (46.8 g, 214 mmol) followed by sodiumbicarbonate (36 g, 428.7 mmol) and water (15 mL). The mixture wasstirred for 16 h, diluted with water (150 mL) and ethyl acetate (150 mL)and transferred to a separatory funnel. This gave three layers; bottom—awhite gelatinous precipitate, middle-light yellow aqueous, top-auburnorganic. The phases were separated collecting the white gelatinousprecipitate and the aqueous layer together. The aqueous was extractedwith ethyl acetate (2×100 mL) and the ethyl acetate extracts werecombined, washed with brine (80 mL), dried over anhydrous sodiumsulfate, filtered and rotary evaporated to give crude product. The crudeproduct was purified by column chromatography (PE:EtOAc=6:1 to 3:1) toget tert-butyl (3-chloro-1H-pyrazo4-yl) carbamate as a white solid.LCMS: RT 0.66 min, m z=218 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 11.04 (br.s, 1H), 7.91 (br. s, 1H), 6.28 (br. s, 1H), 1.52 (s, 9H).

Methyl2-(4-((tert-butoxycarbonyl)amino)-3-chloro-1H-pyrazol-1-yl)-2-methylpropanoate

To a solution of tert-butyl N-(3-chloro-1H-pyrazol-4-yl)carbamate (2 g,9.19 mmol) in DMF (20 mL) was added NaH (404 mg, 10.11 mmol, 60% purity)at 0° C. The mixture was stirred at 25° C. for 1 h. Methyl2-bromo-2-methylpropanoate (1.83 g, 10.11 mmol) was added to the mixtureat 0° C. and stirred at 25° C. for 1 h. The reaction mixture wasquenched by addition of ice water (150 mL) and extracted with EtOAc(3×50 mL). The combined organic layers were washed with saturated brine(3×50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give methyl2-(4-((tert-butoxycarbonyl)amino)-3-chloro-1H-pyrazol-1-yl)-2-methylpropanoateas a yellow oil. LCMS: RT 0.849 min, m/z=318.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 7.92 (s, 1H), 6.25 (s, 1H), 3.70 (s, 3H), 1.81 (s, 6H), 1.52(s, 9H).

tert-butyl(1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-chloro-1H-pyrazol-4-yl)carbamate

A solution of methyl2-[4-(tert-butoxycarbonylamino)-3-chloro-pyrazol-1-yl]-2-methyl-propanoate(3 g, 9.44 mmol) in methanol (50 mL) saturated with NH₃ was stirred at80° C. for 16 h in a 100 mL of sealed tube. The reaction mixture wasconcentrated under reduced pressure to give tert-butyl(1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-chloro-1H-pyrazol-4-yl)carbamateas a yellow gum. LCMS: RT 0.736 min, m/z=303.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 7.99 (s, 1H), 6.30 (br. s., 1H), 5.92 (br. s., 1H), 5.58 (br.s., 1H), 1.82 (s, 6H), 1.51 (s, 9H).

tert-butyl (3-chloro-1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)carbamate

To a solution of tert-butyl(1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-chloro-1H-pyrazol-4-yl)carbamate(200 mg, 660.59 μmol) in pyridine (3 mL) was added POCl₃ (152 mg, 990.89μmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reactionmixture was quenched by addition of water (30 mL) at 0° C. and thenextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give tert-butyl(3-chloro-1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)carbamate as a redsolid. LCMS: RT 0.837 min, m/z=285.2 [M+H]⁺.

2-(3-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-17)

A mixture of tert-butyl(3-chloro-1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)carbamate (150 mg,526.80 μmol),4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (175 mg,526.80 μmol) and PTSA (226.79 mg, 1.32 mmol) in 1,4-dioxane (3 mL) wasstirred at 100° C. for 2 h. The reaction mixture was concentrated underreduced pressure to give a residue. The residue was diluted with H₂O (20mL), adjusted to pH=8 by aq. NaHCO₃ and then extracted with EtOAc (3×10mL). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-HPLC (neutral condition) to givetitle compound2-(3-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-17). ¹H NMR (400 MHz, CDCl₃): δ 8.50 (br. s., 1H), 8.31 (br. s., 1H),6.95 (br. s., 1H), 2.28 (br. s., 1H), 2.02 (s, 6H), 1.11-1.37 (m, 4H).HPLC: RT: 3.70 min. MS: m/z: 371.1 [M+H]⁺.

Example A-15 Synthesis of1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propan-2-oland1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-2-methyl-propan-2-ol(A-18 and A-19) 2-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)propan-2-oland 2-methyl-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol

To a mixture of 3-methyl-4-nitro-1H-pyrazole (1.50 g, 11.80 mmol) and2,2-dimethyloxirane (2.43 g, 33.75 mmol, 3 mL) in DMF (19 mL) was addedCs₂CO₃ (7.69 g, 23.60 mmol) at 25° C. then heated to 100° C. and stirredfor 3 h. The mixture was cooled to 25° C. and poured into water (100 mL)then extracted with EtOAc (5×40 mL), washed with brine (3×20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a mixture of compound2-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)propan-2-ol and2-methyl-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol as a red brownoil. LCMS: RT 0.485 min, m/z=200.2 [M+H]⁺.

1-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol and1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol

A solution of the mixture2-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)propan-2-ol and2-methyl-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (1.00 g, 5.02mmol) in EtOH (20 mL) was treated with Pd/C (10%, 0.3 g). The suspensionwas degassed and purged with H₂ for 3 times. The mixture was stirredunder H₂ (15 PSI) at 25° C. for 16 h. The reaction mixture was filteredand concentrated under reduced pressure to give the mixture compound1-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol and1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a brown oil.LCMS: RT 0.111 min, m/z=170.2 [M+H]⁺.

1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propan-2-oland1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-2-methyl-propan-2-ol

A mixture of 1-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol and1-(4-amino-5-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol) (300 mg, 1.77mmol), 2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (591 mg,1.59 mmol) and Et₃N (537 mg, 5.31 mmol, 736.05 μL) were taken up into amicrowave tube in n-BuOH (3 mL). The sealed tube was heated at 120° C.for 60 min under microwave. The reaction mixture was cooled to 25° C.and filtered. The residue was purified by prep-HPLC (neutral) andfurther separated by SFC to provide1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propan-2-olas a white solid and1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-2-methyl-propan-2-olas a white solid.

1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propan-2-ol(A-19)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.39 (s, 1H), 7.65 (s, 1H), 6.50 (br. s.,1H), 4.40 (s, 1H), 3.98 (s, 2H), 2.26 (s, 1H), 2.19 (s, 3H), 1.24-1.28(m, 1H), 1.19 (s, 8H), 1.04-1.12 (m, 2H). HPLC: RT 2.91 min. MS: [M+H]⁺m/z: 356.2.

1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-2-methyl-propan-2-ol(A-18)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.42 (br. s., 1H), 7.78 (br. s., 1H),6.73 (br. s., 1H), 3.88-4.06 (m, 3H), 2.25 (s, 4H), 1.23-1.28 (m, 2H),1.19 (s, 6H), 1.09-1.15 (m, 2H). HPLC: RT 2.91 min. MS: [M+H]⁺ m/z:356.2.

Example A-16 Synthesis of1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-1-piperidyl]ethanoneand1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-1-piperidyl]ethanone(A-20 and A-21)1-[4-(5-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone and1-[4-(3-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone

To a mixture of 1-(4-hydroxy-1-piperidyl)ethanone (500 mg, 3.49 mmol),3-methyl-4-nitro-1H-pyrazole (487 mg, 3.84 mmol) and PPh₃ (1.37 g, 5.24mmol) in THF (30 mL) was added DIAD (1.06 g, 5.24 mmol) at 0° C. underN₂. The mixture was then stirred at 25° C. for 16 h. The mixture waspoured into ice-water (100 mL) and extracted with EtOAc (3×50 mL). Thecombined organic phase was washed with brine, dried with anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography (PE:EtOAc=1:1) to afford a mixture of1-[4-(5-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone and1-[4-(3-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone as a whitesolid. LCMS: RT 0.603 min, m/z=253.2 [M+H]⁺.

1-[4-(4-amino-5-methyl-pyrazol-1-yl)-1-piperidyl]ethanone and1-[4-(4-amino-3-methyl-pyrazol-1-yl)-1-piperidyl]ethanone

To a mixture of1-[4-(5-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone and1-[4-(3-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone (400 mg, 1.59mmol) was in MeOH (20 mL) added Pd—C (0.2 g) under N₂. The suspensionwas degassed under vacuum and purged with H₂ three times. The mixturewas stirred under H₂ (15 psi) at 25° C. for 1 h. The reaction mixturewas filtered and the filtrate was concentrated to give a mixture1-[4-(4-amino-5-methyl-pyrazol-1-yl)-1-piperidyl]ethanone and1-[4-(4-amino-3-methyl-pyrazol-1-yl)-1-piperidyl]ethanone as adark-brown solid. LCMS: RT 0.731 min, m/z=223.1 [M+H]⁺.

1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-1-piperidyl]ethanoneand1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-1-piperidyl]ethanone(A-20 and A-21)

To a mixture of1-[4-(4-amino-5-methyl-pyrazol-1-yl)-1-piperidyl]ethanone andI-[4-(4-amino-3-methyl-pyrazol-1-yl)-1-piperidyl]ethanone (250 mg, 1.13mmol) in 1,4-dioxane (2 mL) was added4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (150 mg,563 μmol) and p-TsOH (29 mg, 169 μmol) at 25° C. under N₂. The mixturewas then heated to 100° C. and stirred for 2 h. The mixture was cooledto 25° C. and poured into ice-water (30 mL). The aqueous phase wasextracted with EtOAc (20 mL×3). The combined organic phase was washedwith brine, dried with anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by prep-HPLC (neutral), which was further separatedby SFC to give1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-1-piperidyl]ethanone(A-20) and1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-1-piperidyl]ethanone(A-21).

1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]-1-piperidyl]ethanone(A-20)

¹H NMR (400 MHz, CDCl₃): δ 8.37 (s, 1H), 7.63 (br. s., 1H), 6.60 (br.s., 1H), 4.76 (d, J=13.43 Hz, 1H), 4.20 (tt, J=4.20, 11.11 Hz, 1H), 4.01(d, J=13.93 Hz, 1H), 3.18-3.28 (m, 1H), 2.69-2.79 (m, 1H), 2.17-2.31 (m,5H), 2.12-2.16 (m, 3H), 1.90-2.11 (m, 3H), 1.16-1.25 (m, 2H), 1.03-1.10(m, 2H). HPLC: RT 2.413 min. MS: [M+H]⁺ m/z: 409.2.

1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-1-piperidyl]ethanone(A-21)

¹H NMR (400 MHz, CDCl₃): δ 8.43 (br. s., 1H), 7.81 (br. s., 1H), 6.67(br. s., 1H), 4.76 (d, J=14.05 Hz, 1H), 4.25 (tt, J=4.00, 11.37 Hz, 1H),3.96 (d, J=13.80 Hz, 1H), 3.24 (t, J=12.05 Hz, 1H), 2.69-2.84 (m, 1H),2.16-2.28 (m, 6H), 2.15 (s, 3H), 1.84-2.02 (m, 2H), 1.24-1.28 (m, 2H),1.14 (br. s., 2H). HPLC: RT 2.406 min. MS: [M+H]⁺ m/z: 409.2.

Example A-17 Synthesis of4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-22 and A-23) 3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one

To a solution of 3-methyl-4-nitro-1H-pyrazole (10 g, 78.68 mmol) in DMF(50 mL) was added portionwise NaH (4.72 g, 118.02 mmol, 60% purity) at0° C. over 30 min. After addition, the mixture was stirred at 20° C. for30 min, and then 3-bromo-3-methylbutan-2-one (15.58 g, 94.42 mmol) wasadded dropwise at 0° C. The resulting mixture was stirred at 20° C. for11 h. The reaction mixture was quenched by addition of H₂O (250 mL) at0° C., and extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography on silica gel (PE/EtOAc=20/1 to 3/1),3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one was obtained asa yellow solid. LCMS: RT 0.674 min, m/z=212 [M+H]+. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.30 (s, 1H) 2.56 (s, 3H) 1.98 (s, 3H) 1.75 (s, 6H).

(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)pent-1-en-3-one

A mixture of 3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one(7.5 g, 35.51 mmol) and DMF-DMA (42.31 g, 355.08 mmol, 47.01 mL) wasstirred at 110° C. for 12 hrs under N₂ atmosphere. The mixture wasconcentrated under reduced pressure to give(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)pent-1-en-3-oneas a yellow solid. The crude product was used in the next step withoutfurther purification. LCMS: RT 0.675 min, m/z=267 [M+H]⁺.

3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazoleand3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyrazole

To a solution of(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)pent-1-en-3-one(10.8 g, 40.56 mmol) in AcOH (100 mL) was added dropwise methylhydrazine(70.07 g, 608.40 mmol, 79.62 mL) at 0° C. over 30 min. The resultingmixture was stirred at 100° C. for 1.5 h. The reaction mixture wasquenched by addition H₂O (100 mL) at 0° C., and then added with sat.NaHCO₃ (200 mL) to pH=8 and extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (PE/EtOAc=20/1 to3/1),3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyrazolewas obtained as an off-white solid, confirmed by HNMR and NOE,3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazolewas obtained as an off-white solid, confirmed by HNMR and NOE.

3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyrazole

¹H NMR (400 MHz, CDCl₁): δ ppm 7.99 (s, 1H) 7.34 (d, J=2.0 Hz, 1H) 6.16(d, J=2.0 Hz, 1H) 3.91 (s, 3H) 2.54 (s, 3H) 1.96 (s, 6H). LCMS: RT 0.701min, m/z=250 [M+H]⁺.

3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazole

¹H NMR (400 MHz, CDCl₃): δ ppm 8.00 (s, 1H) 7.46 (d, J=2.0 Hz, 1H) 6.35(d, J=2.4 Hz, 1H) 3.47 (s, 3H) 2.56 (s, 3H) 1.98 (s, 6H). LCMS: RT 0.673min, m/z=250 [M+H]⁺.

3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-amine

To a solution of3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazole(3 g, 12.04 mmol) in MeOH (60 mL) was added Pd—C (10%, 1.28 g) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 20° C. for 2 hrs.The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to give3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-amineas a brown solid. The crude product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl3): δ ppm 7.39 (d, J=2.0 Hz,1H) 6.78 (s, 1H) 6.26 (d, J=2.0 Hz, 1H) 3.37 (s, 3H) 2.19 (s, 3H) 1.86(s, 6H).

3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine

To a solution of3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyrazole(2 g, 8.02 mmol) in MeOH (40 mL) was added Pd—C (10%, 0.85 g) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 20° C. for 2 hrs.The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to give3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-amineas a brown solid. The crude product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.23 (d, J=2.0 Hz,1H) 6.98 (s, 1H) 5.96 (d, J=2.4 Hz, 1H) 3.87 (s, 3H) 2.60-2.73 (bs, 2H)2.20 (s, 3H) 1.90 (s, 6H).

4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-22)

To a mixture of3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-amine(100 mg, 456.02 μmol) and2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (67.67 mg, 304.01μmol) in 1,4-dioxane (3 mL) was added p-TsOH (15.71 mg, 91.20 μmol) inone portion at 25° C. under N₂. The mixture was heated to 100° C. andstirred for 2 h. The mixture was added with water (5 mL) and thenadjusted to pH=7 by adding NaHCO₃ (3 mL). The reaction mixture was thenextracted with EtOAc (3×4 mL). The combined organic phase was washedwith brine (5 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral condition) to give4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ ppm 8.35-8.43 (m, 1H) 7.57-7.72 (m, 1H)7.41-7.48 (m, 1H) 6.63-6.79 (m, 1H) 6.28-6.38 (m, 1H) 3.42 (s, 3H) 2.27(s, 3H) 2.12-2.23 (m, 1H) 1.95 (s, 6H) 0.90-1.15 (m, 4H). HPLC: RT 2.821min. MS: (M+H⁺) m/z: 406.

4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-23)

To a mixture of3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine(100 mg, 456.02 μmol) and2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (67.67 mg, 304.01μmol) in 1,4-dioxane (3 mL) was added p-TsOH (15.71 mg, 91.20 μmol) inone portion at 25° C. under N₂. The mixture was then heated to 100° C.and stirred for 2 h. The crude product was added with water (5 mL) andthen adjusted to pH=7 by adding NaHCO₃ (3 mL). The reaction mixture wasthen extracted with EtOAc (3×4 mL). The combined organic phase waswashed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral condition) to give4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ ppm 8.30-8.43 (m, 1H) 7.64-7.79 (m, 1H)7.28-7.32 (m, 1H) 6.57-6.84 (m, 1H) 5.94-6.15 (m, 1H) 3.91 (s, 3H) 2.26(s, 3H) 2.14-2.22 (m, 1H) 1.97 (s, 6H) 1.10-1.20 (m, 2H) 1.02-1.10 (m,2H). HPLC: RT 2.817 min. MS: [M+H]⁺ m/z: 406.

Example A-18 Synthesis of4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-24 and A-25) 5-methyl-4-nitro-1-tetrahydropyran-4-yl-pyrazole and3-methyl-4-nitro-1-tetrahydro-2H-pyran-4-yl-pyrazole

To a mixture of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34 mmol) andtetrahydropyran-4-ol (4.82 g, 47.21 mmol, 4.73 mL) in THF (70 mL) wasadded PPh₃ (15.48 g, 59.01 mmol) and DIAD (11.93 g, 59.01 mmol, 11.47mL) in one portion at 0° C. under N₂. The mixture was stirred at 0° C.for 60 min, then warmed to 25° C. and stirred for 16 h. The mixture waspoured into the mixture of PE and EtOAc (PE:EtOAc=1:1) (100 mL),filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EtOAc=5:1) to afford5-methyl-4-nitro-1-tetrahydropyran-4-yl-pyrazole and3-methyl-4-nitro-1-tetrahydro-2H-pyran-4-yl-pyrazole as yellow solids.LCMS: RT 0.610 min, m/z=212.2 [M+H]⁺.

5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-amine and3-methyl-1-tetrahydro-2H-pyran-4-yl-pyrazol-4-amine

To a mixture of 5-methyl-4-nitro-1-(tetrahydropyran-4-yl)-1H-pyrazoleand 3-methyl-4-nitro-1-tetrahydro-2H-pyran-4-yl-pyrazole (3 g, 14.20mmol) in MeOH (60 mL) was added Pd/C (1 g, 10%) under N₂. The suspensionwas degassed under reduced pressure and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 25° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The crude product5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-amine and3-methyl-1-tetrahydro-2H-pyran-4-yl-pyrazol-4-amine was used into thenext step without further purification. LCMS: RT 0.482 min, m/z=182.1[M+H]⁺.

4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-24 and A-25)

5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-amine,3-methyl-1-tetrahydro-pyran-4-yl-pyrazol-4-amine (200 mg, 1.31 mmol),2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (251 mg, 1.13 mmol)and TEA (398 mg, 3.93 mmol, 544.77 μL) were taken up into a microwavetube in n-BuOH (2 mL). The sealed tube was heated at 120° C. for 90 minunder microwave. The mixture was cooled to 25° C. and concentrated underreduced pressure. The residue was poured into ice-water (5 mL). Theaqueous phase was extracted with EtOAc (3×2 mL). The combined organicphase was washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, PE:EtOAc=1:1) to provide4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-aminewas obtained.

4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-24)

¹H NMR (400 MHz, CDCl₃): δ 8.39 (s, 1H), 7.66 (br. s., 1H), 6.28-6.92(m, 1H), 4.12-4.26 (m, 3H), 3.49-3.62 (m, 2H), 2.33 (qd, J=12.40, 4.58Hz, 2H), 2.23 (s, 3H), 1.87 (dd, J=12.80, 2.13 Hz, 2H), 1.23 (br. s.,2H), 1.04-1.12 (m, 2H). HPLC: RT 3.06 min. MS: [M+H]⁺ m/z=368.2.

4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-25)

¹H NMR (400 MHz, CDCl₃): δ 8.42 (br. s., 1H), 7.83 (br. s., 1H),4.23-4.33 (m, 1H), 4.12 (d, J=11.04 Hz, 2H), 3.56 (t, J=11.73 Hz, 2H),2.26 (s, 3H), 1.98-2.17 (m, 4H), 1.25-1.31 (m, 2H), 1.16 (br. s., 2H).HPLC: RT 3.15 min. MS: [M+H]⁺ m/z=368.2.

Example A-19 Synthesis of5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-oneand5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one(A-26 and A-27) 5-((tert-butyldiphenylsilyl)oxy)piperidin-2-one

To a solution of 5-hydroxypiperidin-2-one (4.5 g, 39.09 mmol) in DMF (60mL) was added imidazole (7.98 g, 117.27 mmol), followed by TBDPSCl(16.11 g, 58.64 mmol) at 0° C. The mixture was stirred at 25° C. for 12h. The solution was added with water (120 mL), extracted with EtOAc(3×30 mL). The organic layers were combined, washed with brine (3×20mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto get a residue, which was purified by silica gel chromatography(PE:EtOAc=10:1 to 1:1) to give5-((tert-butyldiphenylsilyl)oxy)piperidin-2-one as an off-white solid.LCMS: RT 0.943 min, m/z=354.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ7.62-7.69 (m, 4H), 7.42-7.48 (m, 2H), 7.36-7.42 (m, 4H), 6.19 (br. s.,1H), 4.06-4.12 (m, 1H), 3.15-3.27 (m, 2H), 2.66 (ddd, J=17.42, 9.48,6.17 Hz, 1H), 2.27 (dt, J=17.86, 5.84 Hz, 1H), 1.74-1.95 (m, 2H),1.02-1.12 (m, 9H).

5-((tert-butyldiphenylsilyl)oxy)-1-methylpiperidin-2-one

To a solution of 5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one (1 g,2.83 mmol) in DMF (15 mL) at 0° C. was added NaH (158.4 mg, 3.96 mmol),the mixture was stirred at 25° C. for 1 h and then CH₃I (802.99 mg, 5.66mmol) was added. The mixture was stirred at 25° C. for 11 h. Thereaction mixture was quenched by addition of H₂O (50 mL), extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine(2×50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue, which was purified by silica gelchromatography (PE:EtOAc=1:1 to 1:3) to give5-((tert-butyldiphenylsilyl)oxy)-1-methylpiperidin-2-one as a yellowoil. LCMS: RT 0.924 min, m/z=368.2 [M+H]⁺.

5-hydroxy-1-methylpiperidin-2-one

To a solution of5-[tert-butyl(diphenyl)silyl]oxy-1-methyl-piperidin-2-one (400 mg, 1.09mmol) in MeOH (15 mL) was added KF (633.29 mg, 10.90 mmol). The mixturewas stirred at 85° C. for 12 h. The reaction mixture was concentratedunder reduced pressure to get a residue, which was slurried withDCM/MeOH (V/V, 10/1, 40 mL), the suspension was filtered and thefiltrate was concentrated to get a residue, which was dissolved in H₂O(20 mL). The solution was extracted with MTBE (2×25 mL), the aqueousphase was concentrated under reduced pressure to give5-hydroxy-1-methyl-piperidin-2-one as a white solid.

1-methyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and1-methyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one

To a solution of 5-hydroxy-1-methyl-piperidin-2-one (175 mg, 1.35 mmol),3-methyl-4-nitro-1H-pyrazole (5) (205.9 mg, 1.62 mmol) and PPh₃ (531.14mg, 2.03 mmol) in THF (15 mL) was added DIAD (409.48 mg, 2.03 mmol) at0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixturewas concentrated under reduced pressure to get a residue, which waspurified by prep-TLC (SiO₂, DCM:MeOH=20:1) to give a mixture of1-methyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and1-methyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one as yellowsolid. LCMS: RT 0.577 min, m/z=239.1 [M+H]⁺.

5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one and5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one

To a mixture of1-methyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and1-methyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one (180 mg,755.54 μmol) in MeOH (10 mL) was added Pd/C (10%, 60 mg) under N₂. Thesuspension was degassed and purged with H₂ for 3 times. The mixture wasstirred under H₂ (15 Psi) at 25° C. for 4 h. It was filtered overcelite, the filter cake was washed with MeOH (20 mL×2), the filtrate wascombined and concentrated under reduced pressure to give a mixture of5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one and5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one (as yellowoil. LCMS: RT 0.194 min, m/z=209.1 [M+H]⁺.

5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-oneand5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one(A-26 and A-27)

A mixture of5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one and5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one (107 mg,513.78 μmol),4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (137 mg,513.78 μmol) and TsOH.H₂O (49 mg, 256.89 μmol) in 1,4-dioxane (15 mL)was degassed and purged with N₂ for 3 times, and then the mixture wasstirred at 100° C. for 2 h under N₂. It was poured into H₂O (15 mL),adjusted to pH=8 with aq. NaHCO₃, extracted with EtOAc (2×30 mL). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to get a residue, which was purified by prep-HPLC(neutral) first and then it was re-purified by SFC to give5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one(14 mg) and5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one.

5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one(A-26)

¹H NMR (400 MHz, CDCl₃): δ 8.39 (s, 1H), 7.67 (br. s., 1H), 6.51 (br.s., 1H), 4.42-4.60 (m, 1H), 3.91 (dd, J=11.69, 9.92 Hz, 1H), 3.46 (ddd,J=12.13, 5.51, 1.76 Hz, 1H), 3.00 (s, 3H), 2.65 (d, J=3.97 Hz, 1H),2.42-2.59 (m, 2H), 2.25 (s, 3H), 2.17 (d, J=1.76 Hz, 2H), 1.22 (br. s.,2H), 1.09 (dd, J=7.72, 3.31 Hz, 2H). HPLC: Retention Time: 2.87 min. MS:(M+H⁺) m/z: 395.2.

5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one(A-27)

¹H NMR (400 MHz, CDCl₁): δ 8.43 (s, 1H), 7.86 (br. s., 1H), 6.49-6.87(m, 1H), 4.56 (d, J=6.62 Hz, 1H), 3.71 (d, J=7.06 Hz, 2H), 3.00 (s, 3H),2.48-2.64 (m, 2H), 2.34-2.45 (m, 1H), 2.17-2.34 (m, 4H), 1.22-1.30 (m,2H), 1.15 (br. s., 2H). HPLC: Retention Time: 2.86 min. MS: (M+H⁺) m/z:395.2.

Example A-20 Synthesis of4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-28 and A-29)1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-4-nitro-pyrazole and1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-4-nitro-pyrazole

To a mixture of 5-methyl-4-nitro-1H-pyrazole (727 mg, 5.72 mmol) and1,3-difluoropropan-2-ol (500 mg, 5.20 mmol) in THF (50 mL) was addedPPh₃ (2.05 g, 7.80 mmol) and DIAD (1.58 g, 7.80 mmol) at 0° C. under N₂.Then the mixture was stirred at 25° C. for 16 h. The mixture was pouredinto ice-water (100 mL) and extracted with EtOAc (3×50 mL). The combinedorganic phase was washed with brine, dried with anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1) to afford a mixture of1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-4-nitro-pyrazole and1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-4-nitro-pyrazole as acolorless oil. LCMS: RT 0.620 min, m/z=206.1 [M+H]⁺.

1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-amine and1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-amine

To a mixture of1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-4-nitro-pyrazole and1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-4-nitro-pyrazole (1 g, 4.87mmol) in EtOH (36 mL) and H₂O (9 mL) was added NH₄Cl (783 mg, 14.64mmol) and Fe (817 mg, 14.64 mmol) at 25° C. under N₂. The mixture wasthen heated to 80° C. and stirred for 2 h. The mixture was cooled to 25°C., filtered and the filtrate was concentrated to afford a mixture of1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-amine and1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-amine as ablack-brown solid. LCMS: RT 0.228 min, m/z=176.1 [M+H]⁺.

4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-28 and A-29)

To a mixture of1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-amine and1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-amine (157 mg, 901μmol) in 1,4-dioxane (3 mL) was added4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (120 mg,450 μmol) and p-TsOH (23 mg, 135 μmol) at 25° C. under N₂. The mixturewas then heated to 100° C. and stirred for 2 h. The mixture was cooledto 25° C. and poured into ice-water (30 mL). The aqueous phase wasextracted with EtOAc (3×20 mL). The combined organic phase was washedwith brine, dried with anhydrous Na₂SO₄, filtered and concentrated. Theresidue was separated by prep-TLC (PE:EtOAc=3:1) to give desiredproducts, which were further purified by prep-HPLC (neutral) to give4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.

4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-28)

¹H NMR (400 MHz, CDCl₃): δ 8.39 (s, 1H), 7.72 (s, 1H), 6.56 (br. s.,1H), 4.77-4.91 (m, 4H), 4.67-4.76 (m, 1H), 2.24 (s, 3H), 2.19 (dd,J=1.57, 4.71 Hz, 1H), 1.22 (br. s., 2H), 1.04-1.13 (m, 2H). HPLC: RT2.870 min. MS: [M+H]⁺ m/z: 362.1.

4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-29)

¹H NMR (400 MHz, CDCl₃): δ 8.43 (br. s., 1H), 7.96 (s, 1H), 6.71 (br.s., 1H), 4.75-4.94 (m, 4H), 4.62-4.72 (m, 1H), 2.26 (s, 4H), 1.26-1.30(m, 2H), 1.14-1.15 (m, 2H). HPLC: Retention Time: 2.871 min. MS: [M+H]⁺m/z: 362.1.

Example A-21 Synthesis of4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-30 and A-31) 1-(2-fluoroethyl)-5-methyl-4-nitro-1H-pyrazole and1-(2-fluoroethyl)-3-methyl-4-nitro-1H-pyrazole

To a solution of 5-methyl-4-nitro-1H-pyrazole (2 g, 15.74 mmol) in DMF(10 mL) was added Cs₂CO₄ (9.74 g, 29.90 mmol) and 1-bromo-2-fluoroethane(5.99 g, 47.21 mmol). The mixture was stirred at 100° C. for 3 h. Thereaction mixture was diluted with H₂O (70 mL) and extracted with EtOAc(3×30 mL). The combined organic layers were washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive 1-(2-fluoroethyl)-5-methyl-4-nitro-1H-pyrazole and1-(2-fluoroethyl)-3-methyl-4-nitro-1H-pyrazole as a pale-yellow oil. Thecrude product was used into the next step without further purification.LCMS: RT 0.377, 0.464 min, m/z=174 [M+H]⁺.

1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-amine and1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-amine

To a solution of 1-(2-fluoroethyl)-5-methyl-4-nitro-1H-pyrazole and1-(2-fluoroethyl)-3-methyl-4-nitro-1H-pyrazole (2 g, 11.55 mmol) in EtOH(48 mL) was added H₂O (12 mL) and NH₄Cl (3.09 g, 57.75 mmol), then Fe(3.23 g, 57.75 mmol). Then the mixture was heated to 80° C. and stirredat 80° C. for 1 h. The mixture was cooled to 25° C., filtered andconcentrated. The aqueous phase was extracted with EtOAc (3×5 mL). Thecombined organic phase was washed with brine (10 mL), dried withanhydrous Na₂SO₄ and concentrated under reduced pressure, to give thecrude product 1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-amine and1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-amine, which was used into thenext step without further purification. LCMS: RT 0.114 min, m/z=144.2[M+H]⁺.

4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-30 and A-31)

To a solution of 1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-amine and1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-amine (161 mg, 1.13 mmol) and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (150 mg,563.40 μmol) in 1,4-dioxane (3 mL) was added p-TsOH (29 mg, 169.02 μmol)under N₂. The mixture was stirred at 100° C. for 2 h. The reactionmixture was quenched by addition of H₂O (15 mL) at 0° C., and then addedwith sat. NaHCO₃ (10 mL) to pH=8 and extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (neutral condition),4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-aminewere obtained.

4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-30)

¹H NMR: (400 MHz, CHLOROFORM-d) δ 8.39 (s, 1H), 7.66 (s, 1H), 6.51 (br,s, 1H), 4.68-4.89 (m, 2H), 4.27-4.43 (m, 2H), 2.12-2.30 (m, 4H),1.18-1.29 (m, 2H), 1.02-1.12 (m, 2H). HPLC: RT 3.07 min. MS: [M+H]₊ m/z:330.2.

4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-31)

¹H NMR: (400 MHz, CHLOROFORM-d) δ 8.43 (s, 1H), 7.86 (s, 1H), 6.66 (br,1H), 4.65-4.86 (m, 2H), 4.27-4.43 (m, 2H), 2.15-2.30 (m, 4H), 1.23-1.33(m, 3H), 1.08-1.18 (m, 2H). HPLC: RT 3.13 min. MS: [M+H]⁺ m/z: 330.2.

Example A-22 Synthesis of2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-32)2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-32)

To a mixture of2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (150 mg,0.94 mmol) in 1,4-dioxane (2 mL) was added2,5-dichloro-4-cyclobutylpyrimidine (186 mg, 0.91 mmol) and p-TsOH (315mg, 1.83 mmol) at 25° C. under N₂. The mixture was stirred at 100° C.for 12 h. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (neutral) to give2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile.¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 8.19 (s, 1H), 6.61 (s, 1H),3.87-3.91 (m, 1H), 2.33-2.47 (m, 4H), 2.30 (s, 3H), 2.09-2.11 (m, 1H),1.94-1.99 (m, 7H). HPLC: RT 3.63 min. MS: [M+H]⁺ m/z: 331.1.

Example A-23 Synthesis of5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(33) and5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(A-34)5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(A-34)

To a mixture of3-methyl-1-[1-methyl-1-(1-methylpyrazol-3-yl)ethyl]pyrazol-4-amine (100mg, 456.02 μmol) and 2,5-dichloro-4-cyclopropyl-pyrimidine (57 mg,304.01 μmol) in 1,4-dioxane (3 mL) was added p-TsOH (15 mg, 91.20 μmol)at 25° C. Then the mixture was heated to 100° C. and stirred for 2 h.The mixture was added to water (5 mL) and adjusted to pH=7 by adding aq.NaHCO₃ (2 mL). Then it was extracted with EtOAc (3 mL×3), washed withbrine (5 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by prep-HPLC (neutral)to give compound5-chloro-4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1-methylpyrazol-3-yl)ethyl]pyrazol-4-yl]pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ ppm 8.12 (s, 1H), 7.71 (s, 1H), 7.28 (d,J=1.51 Hz, 1H), 6.42 (br. s., 1H), 6.04 (s, 1H), 3.91 (s, 3H), 2.35-2.42(m, 1H), 2.25 (s, 3H), 1.96 (s, 6H), 1.02-1.10 (m, 4H). HPLC: RT 2.641min. MS: [M+H]⁺ m/z: 372.2.

Compound A-33 was prepared in analogous manner.

Example A-24 Synthesis of5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(A-35)5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(A-35)

To a solution of 2,5-dichloro-4-cyclopropylpyrimidine (200 mg, 1.06mmol) and3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine(280 mg, 1.27 mmol) in 1,4-dioxane (2 mL) was added TFA (36 mg, 318.00μmol) under N₂. The mixture was stirred at 100° C. for 2 h. The reactionmixture was quenched by addition sat. NaHCO₃ (10 mL) at 0° C., and thendiluted with H₂O (10 mL) and extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (neutral condition) to give5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine.¹H NMR (400 MHz, CHLOROFORM-d): δ 8.13 (s, 1H), 7.97 (s, 1H), 7.88 (s,1H), 6.42 (br, 1H), 3.91 (s, 3H), 2.33-2.45 (m, 1H), 2.23 (s, 3H), 2.04(s, 6H), 1.11-1.16 (m, 2H), 1.04-1.10 (m, 2H). HPLC: RT 2.68 min. MS:[M+H]⁺ m/z: 373.1.

Example A-25 Synthesis ofN-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amineandN-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-36 and A-37) (E)-tert-butyl(3-chloro-1-(1-(((dimethylamino)methylene)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)carbamate

A solution of tert-butylN-[1-(2-amino-1,1-dimethyl-2-oxo-ethyl)-3-chloro-pyrazol-4-yl]carbamate(2 g, 6.61 mmol) in DMF-DMA (20 mL) was degassed and purged with N₂ for3 times, and then the mixture was stirred at 110° C. for 2 h under N₂.The reaction mixture was concentrated under reduced pressure to give(E)-tert-butyl(3-chloro-1-(1-(((dimethylamino)methylene)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)carbamateas a yellow gum. LCMS: RT 0.738 min, m/z=358.2 [M+H]⁺.

tert-butyl(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)carbamateand tert-butyl(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)carbamate

To a solution of (E)-tert-butyl(3-chloro-1-(1-(((dimethylamino)methylene)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)carbamate(2 g, 5.59 mmol) in AcOH (20 mL) was added methylhydrazine (3.86 g,33.54 mmol, 4.39 mL, 40% purity). The mixture was stirred at 95° C. for1 h. The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with water (20 mL), adjusted to pH=8 by aq. NaHCO₃and extracted with EtOAc (3×20 mL). The combined organic layers werewashed with saturated brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by silica gel column chromatography (PE:EtOAc=1:1 to 1:2) togive tert-butyl(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)carbamateand tert-butyl(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)carbamateas a yellow oil. LCMS: RT 0.728 min, m/z=341.2 [M+H]⁺.

N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-36)

A mixture of4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (219 mg,821.57 μmol), tert-butyl(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)carbamate(700 mg, 40% purity, 328.6 μmol) and PTSA (354 mg, 2.05 mmol) in1,4-dioxane (8 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 100° C. for 2 h under N₂. The reactionmixture was concentrated under reduced pressure. The residue was dilutedwith H₂O (60 mL), adjusted to pH=8 by aq. NaHCO₃ and then extracted withEtOAc (3×20 mL). The combined organic layers were washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue, which was purified by prep-HPLC (neutral condition)to giveN-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ 8.42 (br. s., 1H), 7.99 (br. s., 1H), 7.91(br. s., 1H), 7.01 (br. s., 1H), 3.92 (s, 3H), 2.23 (br. s., 1H), 2.04(s, 6H), 1.21 (br. s., 2H), 1.12 (d, J=7.03 Hz, 2H). HPLC: RT: 3.22 min.MS: m/z: 427.2 [M+H]⁺.

N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-37)

A mixture of4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (117 mg,440.13 μmol), tert-butyl(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)carbamate(150 mg, 440.13 μmol) and PTSA (189.48 mg, 1.1 mmol) in dioxane (3 mL)was degassed and purged with N₂ for 3 times, and then the mixture wasstirred at 100° C. for 3 h under N₂. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with H₂O(60 mL), adjusted to pH=8 by aq. NaHCO₃ and then extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by prep-HPLC (neutral condition) togiveN-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ 0.95-1.27 (m, 4H), 2.05 (s, 6H), 2.22 (br.s., 1H), 3.43 (br. s., 3H), 7.07 (br. s., 1H), 7.84 (s, 1H), 8.44 (br.s., 1H). HPLC: RT: 3.24 min. MS: m/z: 427.2 [M+H]⁺.

Example A-26 Synthesis of2-(4-((4-(1-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-38)4-(1-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine

To a solution of 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (300mg, 1.33 mmol) in CH₃CN (9.00 mL) and H₂O (9.00 mL) was added1-fluorocyclopropanecarboxylic acid (125 mg, 1.2 mmol), (NH₄)₂S₂O₈ (1.5g, 6.65 mmol) and AgNO₃ (904 mg, 5.32 mmol). Then the mixture wasstirred at 20° C. for 12 h. The resulting mixture was extracted withEtOAc (3×5 mL). The combined organic extracts were concentrated underreduced pressure. The residue was purified by prep-TLC (SiO₂,PE:EtOAc=1:1) to give4-(1-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidineas a white solid. LCMS: RT 1.28 min, m/z=285.0 [M+H]⁺.

2-(4-((4-(1-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(A-38)

To a solution of4-(1-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine(45 mg, 0.158 mmol) in 1,4-dioxane (1 mL) was added2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (26 mg,0.158 mmol) and p-TsOH (8.2 mg, 0.05 mmol) under N₂. Then the mixturewas stirred at 100° C. for 1 h. The mixture was concentrated underreduced pressure. The residue was purified by prep-HPLC (neutral) togive2-(4-((4-(1-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile.¹H NMR (400 MHz, CHLOROFORM-d): δ 8.67 (br. s., 1H), 7.89-8.21 (m, 1H),6.60-6.96 (m, 1H), 2.27 (s, 3H), 1.99 (s, 6H), 1.56 (br. s., 2H),1.55-1.59 (m, 2H), 1.53 (s, 2H), 1.50-1.55 (m, 1H). HPLC: RT 3.49 min.MS: (M+H⁺) m/z: 369.2.

Example A-27 Synthesis of4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-39) 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-1-ol

To a solution of ethyl2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoate (20 g, 82.9mmol) in MeOH (200 mL) was added NaBH₄ (6.3 g, 165.8 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 2 h. The mixture was cooled to20° C. and poured into sat. NH₄Cl (400 mL). The aqueous phase wasextracted with EtOAc (3×200 mL). The combined organic phase was washedwith brine (200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by silica gel column chromatography (PE:EtOAc=20:1 to 1:1) togive 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-1-ol as ayellow solid. ¹H NMR (400 MHz, CHLOROFORM-d): δ 8.20-8.24 (m, 1H),3.73-3.81 (m, 2H), 3.11 (br. s., 1H), 2.42-2.54 (m, 3H), 1.54 (s, 6H).

2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanal

To a solution of2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-1-ol (5 g, 25 mmol)in DCM (350 mL) was added DMP (11.7 g, 27.6 mmol, in DCM (40 mL)portionwise at 0° C. The reaction mixture was stirred at 20° C. for 12 hunder N₂. Sat. NaHCO₃ and Na₂S₂O₃ were added into the reaction mixture.The resulting mixture was stirred for 0.5 h. The organic phase wasseparated, washed with NaHCO₃, brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by silica gel column chromatography(PE:EtOAc=5:1) to give2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanal as a yellow solid.¹H NMR (400 MHz, CHLOROFORM-d): δ9.56-9.63 (m, 1H), 8.28 (s, 1H), 2.55(s, 3H), 1.70 (s, 6H).

3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole

To a solution of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanal(1.6 g, 8.1 mmol) in MeOH (50 mL) was added dimethyl(1-diazo-2-oxopropyl)phosphonate (3.2 g, 16.2 mmol) and K₂CO (2.3 mg,16.2 mmol) in one portion at 25° C. The reaction mixture was stirred at25° C. for 16 h under N₂. The mixture was cooled to 20° C. and pouredinto ice-water (40 mL). The aqueous phase was extracted with EtOAc (3×40mL). The combined organic phase was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a residue, which was purified by silica gel columnchromatography (PE:EtOAc=10:1) to give3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole as a yellow oil.¹H NMR (400 MHz, CHLOROFORM-d): δ 8.55 (s, 1H), 2.73 (s, 1H), 2.54 (s,3H), 1.84 (s, 6H).

1-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,3-triazole

To a solution of 3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole(200 mg, 1.0 mmol) in t-BuOH (0.5 mL) and water (2 mL) was added CuI (40mg, 0.2 mmol), CH₃I (177 mg, 0.08 mL, 1.3 mmol) and NaN₃ (75 mg, 1.1mmol). The reaction mixture was stirred at 70° C. for 2 h. The reactionmixture was diluted with EtOAc and 35% ammonia (5 mL). The mixture wasstirred for 30 min and the two phase separated. The organic layer wasdried over Na₂SO₄, filtered and evaporated to give a residue, which waspurified by prep-TLC (SiO₂, EtOAc) to give1-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,3-triazoleas a light yellow solid. LCMS: RT 0.645 min, m/z=251.1 [M+H]⁺.

3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-amine

To a solution of1-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,3-triazole(150 mg, 0.6 mmol) in EtOH (8 mL) and water (2 mL) was added Fe (100 mg,1.8 mmol) and NH₄Cl (96 mg, 1.8 mmol), then the mixture was stirred at100° C. for 2 h. The reaction was concentrated under reduced pressure togive residue, which was diluted with EtOAc (2×10 mL) and filtered. Thefiltrate was concentrated under reduced pressure to give the title3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-amineas a yellow oil. LCMS: RT 0.098 min, m/z=221.2 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-39)

To a solution of3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-amine(79 mg, 0.36 mmol) in 1,4-dioxane (2 mL) was added4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (105 mg,0.39 mmol) and TFA (82 mg, 0.05 mL, 0.72 mmol). Then the mixture wasstirred at 100° C. for 2 h. The mixture was concentrated under reducedpressure to give a residue, which was purified by prep-HPLC (neutral) togive4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CHLOROFORM-d): δ8.39 (br. s., 1H), 7.92 (br. s., 1H),7.20 (s, 1H), 6.71 (br. s., 1H), 4.03 (s, 3H), 2.25 (s, 3H), 2.20 (d,J=5.6 Hz, 1H), 2.03 (s, 6H), 1.19 (br. s., 2H), 1.07-1.13 (m, 2H). HPLC:RT 2.88 min. MS: [M+H]⁺ m/z: 407.1.

Example A-28 Synthesis of4-cyclopropyl-N-(3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-40)4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole

To a solution of TMSN₃ (984 mg, 8.5 mmol, 1.2 mL) in MeOH (2.5 mL) andDMF (20 mL) was added3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole (1.1 g, 5.7 mmol)and CuI (109 mg, 0.7 mmol). The reaction mixture was stirred at 110° C.for 12 h under N₂. The mixture was cooled to 20° C. and poured intoice-water (100 mL). The aqueous phase was extracted with EtOAc (3×50mL). The combined organic phase was washed with brine (50 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a residue, which was purified by silica gel columnchromatography (PE:EtOAc=1:1) to give4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole asa yellow oil. LCMS: RT 0.691 min, m/z=237.2 [M+H]⁺.

2-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole

To a solution of4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole (1g, 4.23 mmol) in MeOH (20 mL) was CH₃I (902 mg, 0.4 mL, 6.35 mmol) andCs₂CO₃ (4.2 g, 12.7 mmol) under N₂, then the mixture was stirred at 50°C. for 12 h. The mixture was filtered and filtrate was concentratedunder reduced pressure to give residue, which was purified by prep-TLC(SiO₂, PE:EtOAc=5:1) to give2-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazoleas a yellow solid. LCMS: RT 0.775 min, m/z=251.2 [M+H]⁺.

3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-amine

To a solution of Pd/C (20 mg) in THF (10 mL) was added2-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole(100 mg, 0.4 mmol) under H₂, then the mixture was stirred at 30° C. for12 h. The reaction was concentrated under reduced pressure to give aresidue, which was diluted with EtOAc (2×15 mL) and filtered. Thefiltrate was concentrated under reduced pressure to give3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-amineas a brown solid. LCMS: RT 0.112 min, m/z=221.2 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-40)

To a solution of3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-amine(90 mg, 0.41 mmol) in 1,4-dioxane (1 mL) was added4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (30 mg,0.11 mmol) and TFA (23 mg, 0.02 mL, 0.20 mmol). Then the mixture wasstirred at 100° C. for 2 h. The mixture was concentrated under reducedpressure to give a residue, which was purified by prep-HPLC (neutral) togive4-cyclopropyl-N-(3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CHLOROFORM-d): δ 8.39 (br. s., 1H), 7.81 (br. s., 1H),7.34 (br. s., 1H), 6.69 (br. s., 1H), 4.17 (s, 3H), 2.25 (s, 3H),2.16-2.23 (m, 1H), 1.98 (s, 6H), 1.16 (br. s., 2H), 1.10 (d, J=8.0 Hz,2H). HPLC: RT 2.25 min. MS: [M+H]⁺ m/z: 407.2.

Example A-29 Synthesis of4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-41 and A-42) Ethyl1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate

To a mixture of 3-methyl-4-nitro-1H-pyrazole (2.33 g, 18.35 mmol) in DMF(10 mL) was added NaH (927 mg, 23.18 mmol, 60%) in one portion at 0° C.under N₂. After that ethyl 1-bromocyclobutanecarboxylate (4 g, 19.32mmol) was added and the mixture was stirred at 100° C. for 12 h. Themixture was poured into ice-water (70 mL) and stirred for 5 min. Theaqueous phase was extracted with EtOAc (3×30 mL). The combined organicphase was washed with brine (2×20 mL), dried with anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EtOAc=10:1 to 2:1) togive ethyl 1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate asa white solid. ¹H NMR (400 MHz, CDCl3): δ ppm 8.08-8.20 (m, 1H)4.00-4.22 (m, 2H) 2.54-2.93 (m, 3H) 2.48 (s, 3H) 2.09-2.36 (m, 1H)1.92-2.05 (m, 1H) 1.14-1.25 (m, 3H).

1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylic acid

To a mixture of ethyl1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate (600 mg, 2.37mmol) in THF (10 mL) and water (10 mL) was added LiOH.H₂O (298.34 mg,7.11 mmol) in one portion at 25° C. under N₂. The mixture was stirred at25° C. for 12 h. The mixture was extracted with EtOAc (2×10 mL). And theaqueous phase was adjusted to pH=3 with 1 N HCl, then extracted withEtOAc (3×10 mL). The combined organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure, to give1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylic acid as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.94 (br. s., 1H) 8.14-8.29(m, 1H) 2.89-3.01 (m, 2H) 2.73-2.84 (m, 2H) 2.59-2.69 (m, 1H) 2.55 (s,2H) 2.22-2.48 (m, 1H) 2.03-2.17 (m, 1H).

1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide

To a solution of 1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylicacid (2.4 g, 10.66 mmol) and DMF (30 μL) in DCM (30 mL) was added oxalylchloride (2.71 g, 21.32 mmol) at 0° C. under N₂. The reaction wasstirred at 25° C. for 2 h. Then the mixture was concentrated. Theresidue was taken up in THF (50 mL) and added into NH₃.H₂O (50 mL) at 0°C., and then the reaction mixture was stirred at 25° C. for another 12h. The mixture was extracted with MTBE (3×50 mL). The combined organicphase was washed with brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EtOAc=10:1 to 1:1) togive 1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide as awhite solid.

(E)-N-((dimethylamino)methylene)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide

A mixture of 1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide(1 g, 4.46 mmol) in DMF-DMA (15 mL) was stirred at 95° C. for 2 h. Themixture was concentrated under reduced pressure. And the crude productwas used directly in next step as is. LCMS: RT 0.667 min, m/z=280[M+H]⁺.

1-methyl-3-[1-(4-nitropyrazol-1-yl)cyclobutyl]-1,2,4-triazole and1-methyl-5-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazole

To a mixture of(E)-N-((dimethylamino)methylene)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide(1.25 g, 4.46 mmol) in AcOH (10 mL) was added methyl hydrazine (1.23 g,26.76 mmol, 1.40 mL) in one portion at 25° C. under N₂. The mixture wasstirred at 95° C. for 2 h. The mixture was concentrated and added withwater (20 mL). The aqueous phase was extracted with EtOAc (2-10 mL). Thecombined organic phase was washed with aq. NaHCO₃ (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=50:1to 1:1) to give1-methyl-3-[1-(4-nitropyrazol-1-yl)cyclobutyl]-1,2,4-triazole and1-methyl-5-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazoleas a white solid. LCMS: RT=0.667 min, m/z=263 [M+H]⁺.

3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine

To a solution of1-methyl-3-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazole(500 mg, 1.91 mmol) in MeOH (20 mL) was added Pd/C (50 mg, 10% purity)under N₂. The suspension was degassed under vacuum and purged with H₂three times. The mixture was stirred under H₂ (15 psi) at 25° C. for 2h. The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to give3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine asa yellow oil. LCMS: RT 0.945 min, m/z=263 [M+H]⁺. ¹H NMR (400 MHz,CDCl3): δ ppm 7.93 (s, 1H) 7.08 (s, 1H) 3.86 (s, 4H) 2.86 (dt, J=6.37,3.15 Hz, 2H) 2.17-2.22 (m, 3H) 2.16 (s, 3H) 1.98-2.02 (m, 2H).

4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-41)

To a mixture of3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine(50 mg, 215.26 μmol) and4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (57.31 mg,215.26 μmol) in 1,4-dioxane (3 mL) was added p-TsOH (11.12 mg, 64.58μmol) in one portion at 25° C. under N₂. The mixture was stirred at 110°C. for 5 h. The residue was poured into ice-water (5 mL) and stirred for5 min. The aqueous phase was extracted with EtOAc (2×10 mL). Thecombined organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theproduct was purification by prep-HPLC (NH₄HCO₃) to give4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ ppm 8.32 (br. s., 1H) 7.84-7.94 (m, 1H) 7.75(br. s., 1H) 6.44-6.68 (m, 1H) 3.78-3.89 (m, 3H) 2.85-3.05 (m, 5H) 2.19(s, 3H) 2.13 (br. s., 1H) 1.91-2.03 (m, 2H) 1.51 (s, 2H) 1.15 (br. s.,2H) 0.96-1.05 (m, 2H). HPLC: Retention Time: 2.563 min. MS: [M+H]⁺ m/z:419.

3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine

To a solution of1-methyl-5-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazole(200 mg, 762.57 μmol) in MeOH (10 mL) was added Pd/C (50 mg, 10% purity)under N₂. The suspension was degassed under vacuum and purged with H₂three times. The mixture was stirred under H₂ (15 psi) at 25° C. for 2h. The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to give3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine asa yellow oil.

4-cyclopropyl-N-[3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-42)

To a mixture of3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine(50 mg, 215.26 μmol) and4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (57.31 mg,215.26 μmol) in 1,4-dioxane (5 mL) was added p-TsOH (37.07 mg, 215.26μmol) in one portion at 25° C. under N₂. The mixture was stirred at 110°C. for 5 h. The residue was poured into ice-water (10 mL) and stirredfor 5 min. The aqueous phases were extracted with EtOAc (2×10 mL). Thecombined organic phase was washed with brine (10 mL), dried withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theproduct was purification by HPLC (NH₄HCO₃) to give4-cyclopropyl-N-[3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.1H NMR (400 MHz, CDCl3): δ ppm 8.39 (s, 1H) 7.89 (s, 1H) 7.49-7.67 (m,1H) 6.65 (br. s., 1H) 3.58 (s, 3H) 3.08-3.18 (m, 2H) 2.97-3.06 (m, 2H)2.29 (s, 3H) 1.96-2.22 (m, 3H) 1.10 (dd, J=7.72, 2.87 Hz, 4H). HPLC: RT3.19 min. MS: [M+H]⁺ m/z: 419.

Example A-30 Synthesis of5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]pyrimidin-2-amineand5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]pyrimidin-2-amine(A-43 and A-44)5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]pyrimidin-2-amineand5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]pyrimidin-2-amine(A-43 and A-44)

To a solution of 2,5-dichloro-4-cyclopropylpyrimidine (120 mg, 634.79μmol) and a mixture1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-amine and1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-amine (56 mg, 317.4μmol) in 1,4-dioxane (5 mL) was added p-TsOH (164 mg, 952.19 μmol). Themixture was stirred at 100° C. for 4 h. The reaction mixture wasconcentrated under reduced pressure. The residue was basified to pH=7with aq. Na₂HCO₃ solution, extracted with EtOAc (3-10 mL). The organiclayers were combined, washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a crudeproduct, which was purified by prep-TLC (PE:EtOAc=1:1), to give twoseparated crude product, which was further purified by prep-HPLC(neutral) to give5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]pyrimidin-2-amineand5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]pyrimidin-2-amine.

5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]pyrimidin-2-amine(A-43)

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 1H), 7.72 (s, 1H), 6.21 (br. s.,1H), 4.90 (d, J=6.02 Hz, 2H), 4.67-4.81 (m, 3H), 2.34-2.42 (m, 1H), 2.23(s, 3H), 1.11-1.17 (m, 2H), 1.03-1.10 (m, 2H). HPLC: RT 3.09 min. MS:[M+H]⁺ m/z: 328.2.

5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]pyrimidin-2-amine(A-44)

¹H NMR (400 MHz, CDCl₃): δ 8.17 (s, 1H), 7.94 (s, 1H), 6.41 (br. s.,1H), 4.76-4.93 (m, 4H), 4.60-4.75 (m, 1H), 2.37-2.47 (m, 1H), 2.25 (s,3H), 1.17-1.23 (m, 2H), 1.09-1.16 (m, 2H). HPLC: RT 3.14 min. MS: [M+H]⁺m/z: 328.2.

Example A-31 Synthesis ofN-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amineandN-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-45 and A-46)N-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amineandN-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-45 and A-46)

To a mixture of5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-amine and3-chloro-1-(1,3-difluoropropan-2-yl)-1H-pyrazol-4-amine (110 mg, 562.37μmol) and 4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine(100 mg, 374.91 μmol) in 1,4-dioxane (3 mL) was added p-TsOH (19 mg,112.47 μmol) at 25° C. under N₂. The mixture was heated to 100° C. andstirred for 2 h. The mixture was cooled to 25° C. and adjusted to pH=7-8with a solution of NaHCO₃ then extracted with EtOAc (3×5 mL). Thecombined organics were washed with brine (5 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (neutral) to giveN-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amineandN-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.

N-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-45)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.45 (s, 1H) 8.11 (s, 1H) 6.72 (br. s.,1H) 4.75-5.02 (m, 5H) 2.24 (br. s., 1H) 1.27-1.32 (m, 2H) 1.15 (dd,J=7.72, 3.31 Hz, 2H). HPLC: RT 3.113 min. MS: [M+H] m z: 382.1.

N-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-46)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.48 (br. s., 1H) 8.10 (br. s., 1H) 6.91(br. s., 1H) 4.64-4.95 (m, 5H) 2.26 (br. s., 1H) 1.27-1.33 (m, 2H) 1.18(br. s., 2H). HPLC: RT 3.159 min. MS: [M+H]⁺ m/z: 382.2.

Example A-32 Synthesis of1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]cyclopropanecarbonitrile(A-47) 1-(4-amino-3-methyl-pyrazol-1-yl)cyclopropanecarbonitrile

To a mixture of1-(3-methyl-4-nitro-pyrazol-1-yl)cyclopropanecarbonitrile (100 mg,520.37 μmol) in EtOH (2 mL) and H₂O (500 μL) was added NH₄Cl (139 mg,2.60 mmol) and Fe (145 mg, 2.60 mmol) at 20° C. The mixture was thenheated to 80° C. and stirred for 1 h. The mixture was cooled to 20° C.,filtered and concentrated. The residue was added with water (10 mL) andthen extracted with EtOAc (3×3 mL), washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure, togive 1-(4-amino-3-methyl-pyrazol-1-yl)cyclopropanecarbonitrile as abrown oil. LCMS: RT 0.107 min, m/z=163.2 [M+H]⁺.

1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]cyclopropanecarbonitrile(A-47)

To a mixture of1-(4-amino-3-methyl-pyrazol-1-yl)cyclopropanecarbonitrile (11 mg, 684.38μmol) and 4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine(121 mg, 456.25 μmol) in 1,4-dioxane (3 mL) was added p-TsOH (23 mg,136.88 μmol) at 25° C. under N₂. The mixture was heated to 100° C. andstirred for 2 h. The mixture was cooled to 25° C. and adjusted pH=7-8 byadding aq.NaHCO₃. Then the mixture was extracted with EtOAc (3×5 mL),washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral) to give compound1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]cyclopropanecarbonitrile.LCMS: RT 0.898 min, m/z=349.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm8.46 (br. s., 1H), 8.02 (br. s., 1H), 6.68 (br. s., 1H), 2.26 (s, 4H),1.80 (d, J=5.73 Hz, 4H), 1.29 (br. s., 2H), 1.17 (br. s., 2H). HPLC: RT2.826 min. MS: [M+H]⁺ m/z: 349.2.

Example A-33 Synthesis ofN-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-48)5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-amine

To a solution of(3S,4S)-4-(5-chloro-4-nitro-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperidine(150 mg, 492.27 μmol) in EtOH (2 mL) and water (500 μL) was added Fe(82.48 mg, 1.48 mmol) and NH₄Cl (79 mg, 1.48 mmol). The reaction wasstirred at 90° C. for 2 h. The reaction solution was concentrated underreduced pressure to give residue, which was washed with EtOAc (2×5 mL)and filtered. The filtrate was concentrated under reduced pressure togive5-chloro-1-[(3S,4S)-3-fluoro-1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-amineas a brown solid, which was used without further purification.

N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-48)

To a solution of4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (130 mg,0.5 mmol) in 1,4-dioxane (2 mL) was added5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-amine(134 mg, 0.5 mmol) and p-TsOH (25 mg, 0.15 mmol) at 25° C. The solutionwas heated at 100° C. for 1 h. The mixture was concentrated underreduced pressure. The residue was purified by prep-HPLC (neutralcondition) to giveN-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CHLOROFORM-d): δ 8.43 (s, 1H), 8.07 (s, 1H), 6.70 (br.s., 1H), 4.93-5.14 (m, 1H), 4.56-4.74 (m, 4H), 4.24-4.36 (m, 1H), 3.66(quin, J=6.39 Hz, 1H), 3.16-3.26 (m, 1H), 2.85 (d, J=9.70 Hz, 1H),2.28-2.43 (m, 1H), 2.22 (br. s., 1H), 1.97-2.17 (m, 4H), 1.23-1.34 (m,3H), 1.09-1.17 (m, 2H). HPLC: RT 2.851 min. MS: [M+H]⁺ m/z: 461.1.

Example A-34 Synthesis of2-(5-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-methylcyclopentanol(A-49 and A-50)2-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-methylcyclopentanol (A-34-2)

To a solution of2-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-methylcyclopentanol (150 mg, 0.61mmol) in EtOH (2 mL) and H₂O (500 μL) was added Fe (102 mg, 1.83 mmol)and NH₄Cl (98 mg, 1.83 mmol). The reaction mixture was stirred at 90° C.for 1 h. The reaction mixture was concentrated under reduced pressure togive a residue, which was diluted with EtOAc (2×3 mL) and filtered. Thefiltrate was concentrated to give2-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-methylcyclopentanol as brownsolid. LCMS: RT 0.113 min, m/z=216.1 [M+H]⁺.

2-(5-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-methylcyclopentanol(A-49, A-50)

To a solution of4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (150 mg,0.56 mmol) in dioxane (2 mL) was added2-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-methylcyclopentanol (122 mg, 0.56mmol) and p-TsOH (29 mg, 0.17 mmol) at 25° C. Then the mixture wasstirred at 100° C. for 1 h. The mixture was concentrated under reducedpressure to give a residue, which was purified by prep-HPLC (NH₄HCO₃) togive 48 mg of crude product, which was further purified by chiral SFC togive two peaks of target isomers, peak 1 and peak 2.

¹H NMR (400 MHz, CHLOROFOR-d): δ 8.42 (s, 1H), 7.99 (s, 1H), 6.81 (br.s., 1H), 4.63 (t, J=7.2 Hz, 1H), 2.35-2.48 (m, 2H), 2.22 (br. s., 1H),1.90-2.07 (m, 3H), 1.71-1.81 (m, 1H), 1.25-1.30 (m, 2H), 1.12 (dd,J=8.0, 3.09 Hz, 2H), 0.97 (s, 3H). HPLC: RT 3.043 min. MS: [M+H]⁺ m/z:402.1.

¹H NMR (400 MHz, CHLOROFOR-d): δ 8.42 (s, 1H), 8.00 (s, 1H), 6.77 (br.s., 1H), 4.63 (t, J=7.2 Hz, 1H), 2.35-2.48 (m, 2H), 2.22 (br. s., 1H),1.87-2.08 (m, 3H), 1.72-1.81 (m, 1H), 1.24-1.30 (m, 2H), 1.12 (dd,J=7.2, 3.31 Hz, 2H), 0.97 (s, 3H). HPLC: Retention Time: 3.045 min. MS:[M+H]⁺ m/z: 402.1.

Example A-35 Synthesis of4-cyclopropyl-N-(1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-51)1-ethyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole

To a solution of3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole (2g, 8.47 mmol) in CH₃CN (30 mL) was added EtI (1.59 g, 10.16 mmol, 813μL) and Cs₂CO₃ (2.76 g, 8.47 mmol). The mixture was stirred at 50° C.for 12 h. The reaction mixture was filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=5:1 to 0:1) to give1-ethyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazoleas a yellow solid. LCMS: RT 0.684 min, m/z=265 [M+H]+.

1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine

To a solution ofI-ethyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole(1.67 g, 6.32 mmol) in EtOH (35 mL) was added Pd—C (10%, 0.67 g) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 50° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to give1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amineas a brown solid. The crude product was used into the next step withoutfurther purification.

4-cyclopropyl-N-(1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-51)

To a solution of4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (70 mg,262.92 μmol) and1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine(62 mg, 262.92 μmol) in 1,4-dioxane (3 mL) was added p-TsOH (14 mg,78.88 μmol). The mixture was stirred at 100° C. for 2 h. The reactionmixture was diluted with H₂O (15 mL) and adjusted with sat. NaHCO₃ topH=9 and extracted with EtOAc (3×10 mL). The combined organic layerswere washed with brine (5 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral condition) to give4-cyclopropyl-N-(1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR: (400 MHz, CHLOROFORM-d) δ 8.38 (s, 1H), 7.99 (s, 1H), 7.86 (s,1H), 6.78 (br, s, 1H), 4.20 (q, J=14.4, 7.2 Hz, 2H), 2.14-2.28 (m, 4H),2.04 (s, 6H), 1.53 (t, J=7.2 Hz, 3H), 1.17-1.25 (m, 2H), 1.02-1.12 (m,2H). HPLC: RT 2.626 min. MS: [M+H]⁺ m/z: 421.2.

Example A-36 Synthesis of4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-52)3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]pyrazol-4-amine

To a solution of1-methyl-3-(1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclopropyl)-1H-1,2,4-triazole(150 mg, 604.25 μmol) in EtOH (20 mL) was added Pd—C (10%, 20 mg) underN₂. The suspension was degassed under reduced pressure and purged withH₂ several times. The mixture was stirred under H₂ (15 psi) at 45° C.for 6 h. The reaction mixture was filtered and the filtrate wasconcentrated, to give the crude3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]pyrazol-4-aminewhich was used into the next step without further purification. LCMS: RT0.822 min, m/z=219.3 [M+H]⁺.

4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-52)

To a mixture of1-methyl-3-(1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclopropyl)-1H-1,2,4-triazole(87 mg, 326.77 μmol) and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (71 mg,326.77 μmol) in 1,4-dioxane (4 mL) was added TFA (112 mg, 980.31 μmol,73 μL) at 20° C. under N₂. The mixture was heated to 80° C. and stirredfor 5 h. The mixture was cooled to 20° C. and was adjusted to pH=8 byadding aq.NaHCO₃ and extracted with EtOAc (3×5 mL). The combined organicphase was washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (neutral) to give4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ 8.41 (br. s., 1H), 8.00 (br. s., 1H), 7.88(s, 1H), 6.71 (br. s., 1H), 3.82 (s, 3H), 2.28 (s, 3H), 2.17-2.25 (m,1H), 1.74 (d, J=4.64 Hz, 4H), 1.26 (br. s., 2H), 1.08-1.14 (m, 2H).HPLC: Retention Time: 2.362 min. MS: (M+H⁺) m/z=405.2.

Example A-37 Synthesis of5-bromo-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(A-53) 5-bromo-2-chloro-4-cyclopropylpyrimidine

To a solution of 5-bromo-2-chloropyrimidine (5 g, 25.9 mmol) in H₂O (150mL) and CH₃CN (150 mL) was added cyclopropanecarboxylic acid (2.2 g,25.9 mmol), (NH₄)₂S₂O₈ (14.8 g, 164.6 mmol) and AgNO₃ (8.8 g, 8.8 mmol).The reaction mixture was stirred at 20° C. for 72 h. The reaction wasquenched by ice water slowly and then extracted with EtOAc (3×150 mL).The combined organic phase was washed with brine (150 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by prep-TLC (SiO₂, PE:EtOAc=10:1) togive 5-bromo-2-chloro-4-cyclopropylpyrimidine as a pale yellow oil. MS:m/z=234.9 [M+H]⁺.

5-bromo-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(A-23)

To a solution of 5-bromo-2-chloro-4-cyclopropylpyrimidine (120 mg, 0.51mmol) in 1,4-dioxane (1 mL) was added3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine(113 mg, 0.51 mmol) and p-TsOH (27 mg, 0.15 mmol). The reaction mixturewas stirred at 100° C. for 2 h. The mixture was concentrated underreduced pressure to give a residue, which was purified by prep-TLC(SiO₂, PE:EtOAc=1:1) to give5-bromo-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine.¹HNMR (400 MHz, CHLOROFORM-d): δ 8.22 (s, 1H), 7.95 (s, 1H), 7.87 (s,1H), 6.39 (br. s., 1H), 3.90 (s, 3H), 2.34-2.43 (m, 1H), 2.22 (s, 3H),2.03 (s, 6H), 1.10-1.14 (m, 2H), 1.03-1.08 (m, 2H). HPLC: RT 2.70 min.MS: [M+H]⁺ m/z: 417.1.

Example A-38 Synthesis of4-cyclopropyl-N-[5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-54) 5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-amine

To a solution of5-methyl-1-[(1-methylpyrazol-3-yl)methyl]-4-nitro-pyrazole (540 mg, 2.44mmol) in MeOH (30 mL) was added Pd—C (10%, 250 mg) under N₂ at 20° C.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 40° C. for 5 h. Themixture was cooled to 20° C. and concentrated to give5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-amine as a whitesolid. LCMS: RT 0.882 min, m/z=192.3 [M+H]⁺.

4-cyclopropyl-N-[5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-54)

To a mixture of 5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-amine(80 mg, 418.34 μmol) and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (123 mg,460.17 μmol) in 1,4-dioxane (1.00 mL) was added TFA (95 mg, 836.68 μmol,61 μL) at 20° C. The mixture was then heated to 100° C. and stirred for3 h. The mixture was cooled to 20° C. and concentrated. The residue wasadjusted pH=7-8 by adding aq. NaHCO₃, then was extracted with EtOAc (3×3mL), washed with brine (3 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral) to give4-cyclopropyl-N-[5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.LCMS: RT 0.882 min, m/z=192.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm8.37 (s, 1H), 7.64 (br. s., 1H), 7.28-7.29 (m, 1H), 6.51 (br. s., 1H),6.08 (br. s., 1H), 5.27 (s, 2H), 3.87 (s, 3H), 2.13-2.25 (m, 4H), 1.20(br. s., 2H), 1.02-1.09 (m, 2H). HPLC: RT 2.489 min. MS: [M+H]⁺ m/z:378.1.

Example A-39 Synthesis of4-cyclopropyl-N-(3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-55) 3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-amine

To a solution of5-methyl-1-[(1-methylpyrazol-3-yl)methyl]-4-nitro-pyrazole (120 mg,542.45 μmol) in MeOH (4 mL) was added Pd—C (10%, 0.05 g) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 40° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to get3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-amine as ablack brown oil. LCMS: RT 0.765 min, m/z=214.2 [M+Na]⁺. ¹H NMR (400 MHz,CDCl₃): δ 7.00 (s, 1H), 6.14 (d, J=2.21 Hz, 1H), 5.12 (s, 2H), 3.87 (s,3H), 2.71 (d, J=7.06 Hz, 2H), 2.18 (s, 3H).

4-cyclopropyl-N-(3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-55)

To a mixture of3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-amine (100mg, 522.93 μmol) and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (139 mg,522.93 μmol) in 1,4-dioxane (2 mL) was added TFA (119 mg, 1.05 mmol) andthen the mixture was stirred at 100° C. for 2 h under N₂. The reactionmixture was concentrated under reduced pressure to give a residue, whichwas purified by prep-HPLC (neutral condition) to give4-cyclopropyl-N-(3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl3): δ 8.38 (br. s., 1H), 7.74 (br. s., 1H), 7.30(br. s., 1H), 6.76 (br. s., 1H), 6.19 (s, 1H), 5.23 (s, 2H), 3.90 (s,3H), 2.24 (s, 3H), 2.18 (d, J=8.16 Hz, 1H), 1.19 (br. s., 2H), 1.07 (dd,J=7.53, 3.26 Hz, 2H). HPLC: RT 2.93 min. MS: [M+H]⁺ m/z=378.1.

Example A-40 Synthesis of4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-56) 3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one

To a solution of 3-methyl-4-nitro-1H-pyrazole (10 g, 78.68 mmol) in DMF(50 mL) was added portionwise NaH (4.72 g, 118.02 mmol, 60% purity) at0° C. over a period of 30 min under N₂. The reaction mixture was warmedto 20° C. and stirred at 20° C. for 1 h. Then3-bromo-3-methyl-butan-2-on56e (15.58 g, 94.41 mmol) was added dropwiseat 0° C. over a period of 30 min. The reaction mixture was warmed to 20°C. and stirred at 20° C. for another 5 h. The reaction mixture wasquenched by pouring into ice water (350 mL) slowly and then extractedwith EtOAc (3×100 mL). The combined organic layers were washed withbrine (2×50 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1 to 3:1) to give3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one as a lightyellow solid. LCMS: RT 0.670 min, m/z=212.2 [M+H]⁺.

1-bromo-3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one

A mixture of 3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one (6.7g, 31.72 mmol), CuBr₂ (12.04 g, 53.92 mmol) in EtOAc (80 mL) and CHCl₃(80 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 80° C. for 24 h under N₂. The reaction mixturewas filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EtOAc=10:1 to 3:1) togive 1-bromo-3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one asa yellow solid. LCMS: RT 1.035 min, m/z=290.0 [M+H]⁺.

3-methyl-1-(2-(2-(methylthio)-1H-imidazol-4-yl)propan-2-yl)-4-nitro-1H-pyrazole

To a mixture of1-bromo-3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one (10 g,34.47 mmol) and 2-Methyl-2-thiopseudourea sulfate (2:1) (11.51 g, 41.36mmol) in EtOH (200 mL) was added AcONa (8.48 g, 103.41 mmol) at 20° C.Then the mixture was heated to 90° C. and stirred for 12 h. The mixturewas cooled to 20° C., quenched by pouring into ice-water (50 mL),concentrated under reduced pressure, and extracted with EtOAc (3×20 mL).The combined organic phase was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=10:1to 3:1) to give3-methyl-1-(2-(2-(methylthio)-1H-imidazol-4-yl)propan-2-yl)-4-nitro-1H-pyrazoleas a yellow solid. LCMS: RT 0.664 min, m/z=282.1 [M+H]⁺.

1-(2-(1H-imidazol-4-yl)propan-2-yl)-3-methyl-4-nitro-1H-pyrazole

To a solution of3-methyl-1-[1-methyl-1-(2-methylsulfanyl-1H-imidazol-4-yl)ethyl]-4-nitro-pyrazole(1 g, 3.55 mmol) in THF (20 mL) was added Et₃SiH (1.24 g, 10.66 mmol)and Pd/C (756 mg, 710.91 μmol, 10% purity) at 0° C. The mixture wasstirred at 20° C. for 60 h. The reaction mixture was filtered andconcentrated under reduced pressure. The residue was purified by flashsilica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column,Eluent of 0-100% EtOAc/PE gradient at 100 mL/min) to give1-(2-(1H-imidazol-4-yl)propan-2-yl)-3-methyl-4-nitro-1H-pyrazole as ayellow solid. LCMS: RT 0.186 min, m/z=236.2 [M+H]⁺.

3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-4-nitro-1H-pyrazole

To a solution of1-[1-(1H-imidazol-4-yl)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole (120mg, 510.12 μmol) in CH₃CN (2 mL) was added Mel (87 mg, 612.14 μmol) andCs₂CO₃ (166 mg, 510.12 μmol). The mixture was stirred at 20° C. for 12h. The reaction mixture was filtered and concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, EtOAc) to give3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-4-nitro-1H-pyrazoleas a yellow solid. LCMS: RT 0.236 min, m/z=250.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ ppm 8.05-8.11 (m, 1H), 7.41-7.48 (m, 1H), 6.82-6.89 (m,1H), 3.70 (s, 3H), 2.54 (s, 3H), 1.94 (s, 6H).

3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-pyrazol-4-amine

To a solution of3-methyl-1-[1-methyl-1-(1-methylimidazol-4-yl)ethyl]-4-nitro-pyrazole(150 mg, 601.76 μmol) in MeOH (10 mL) was added Pd—C (10%, 128 mg) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 30° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to give3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-pyrazol-4-amineas a brown oil. LCMS: RT 0.387 min, m/z=220.3 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-56)

To a solution of3-methyl-1-[1-methyl-1-(1-methylimidazol-4-yl)ethyl]pyrazol-4-amine (120mg, 547.22 μmol) and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (146 mg,547.22 μmol) in 1,4-dioxane (5 mL) was added TFA (31 mg, 273.61 μmol).The mixture was stirred at 100° C. for 1 h. The reaction mixture wasdiluted with H₂O (20 mL) and aq. NaHCO₃ (20 mL), extracted with EtOAc(3×10 mL). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-HPLC (neutral condition) to give4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ ppm 8.30-8.47 (m, 1H), 7.74-7.94 (m, 1H),7.36-7.45 (m, 1H), 6.53-6.78 (m, 2H), 3.65 (s, 3H), 2.26 (s, 3H),2.14-2.23 (m, 1H), 1.96 (s, 6H), 1.15-1.28 (m, 2H), 1.03-1.12 (m, 2H).HPLC: RT 2.467 min. MS: m/z: 406.2 [M+H]⁺.

Example A-41 Synthesis of1-[5-chloro-4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]-2-methyl-propan-2-ol(A-57)

To a mixture of 1-(4-amino-5-chloro-1H-pyrazol-1-yl)-2-methylpropan-2-ol(70 mg, 369.12 μmol) and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (98 mg,369.12 μmol) in 1,4-dioxane (5 mL) was added TFA (84 mg, 738.24 μmol, 55μL) at 20° C. under N₂. The mixture was heated to 90° C. and stirred for5 h. The mixture was cooled to 20° C. and adjusted to pH=8 by adding aq.NaHCO₃. The aqueous phase was extracted with EtOAc (3×10 mL). Thecombined organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-HPLC (neutral) to give1-[5-chloro-4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]-2-methyl-propan-2-ol.¹H NMR (400 MHz, CDCl₃): δ 8.11 (d, J=9.66 Hz, 2H), 7.87 (s, 1H), 6.68(br. s., 1H), 5.13-5.25 (m, 1H), 3.81 (s, 3H), 3.05 (d, J=4.14 Hz, 3H),2.28 (s, 3H), 1.73 (s, 4H). HPLC: RT 2.723 min. MS: [M+H]⁺ m/z=376.1.

Example A-42 Synthesis ofN-(1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-58)1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine

To a solution of3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole (2g, 8.47 mmol) in EtOH (40 mL) was added Pd—C (10%, 0.9 g) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 50° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to give1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine asa brown solid. The crude product was used into the next step withoutfurther purification.

N-(1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-58)

To a solution of4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (129 mg,484.85 μmol) and1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine(100 mg, 484.85 μmol) in 1,4-dioxane (5 mL) was added TFA (110 mg,969.70 μmol). The mixture was stirred at 100° C. for 2 h. The reactionmixture was diluted with H₂O (20 mL), adjusted with sat. NaHCO₃ (10 mL)to pH=8-9 and extracted with EtOAc (3×10 mL). The combined organiclayers were washed with brine (5 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by prep-HPLC (FA condition) to give an FA salt of the product(36 mg). The salt was purified by prep-HPLC (neutral) to giveN-(1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR: (400 MHz, CDCl3): (400 MHz, CHLOROFORM-d) δ 11.39 (bs, 1H), 8.41(s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.03 (bs, 1H), 2.27 (s, 3H),2.18-2.25 (m, 1H), 2.05 (s, 6H), 1.20-1.30 (m, 2H), 1.07-1.18 (m, 2H).HPLC: RT 2.301 min. MS: [M+H]⁺ m/z: 393.2.

Example A-43 Synthesis of(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,and(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one(A-59, A-60, A-61, and A-62)5-((tert-butyldiphenylsilyl)oxy)-1-ethylpiperidin-2-one

To a solution of 5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one (2 g,5.66 mmol) in DMF (10 mL) was added portionwise NaH (340 mg, 8.49 mmol,60% purity) at 0° C. over 20 min. After addition, the mixture wasstirred at 20° C. for 40 min, and then EtI (1.32 g, 8.49 mmol) was addeddropwise at 0° C. The resulting mixture was stirred at 20° C. for 11 h.The reaction mixture was poured into ice-water (80 mL) and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with brine(3×10 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=5:1 to 0:1) to give5-((tert-butyldiphenylsilyl)oxy)-1-ethylpiperidin-2-one as a yellow oil.LCMS: RT 1.008 min, m/z=382.2 [M+H]⁺.

1-ethyl-5-hydroxypiperidin-2-one

To a solution of5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-piperidin-2-one (1.5 g, 3.93mmol) in MeOH (30 mL) was added KF (4.57 g 78.60 mmol) at 25° C. underN₂. The mixture was then heated to 70° C. and stirred for 48 h. Themixture was cooled to 25° C. and concentrated under reduced pressure.The residue was poured into DCM:MeOH=10:1 (50 mL) and stirred for 30min, followed by filtration. The filtrate was concentrated under reducedpressure. The residue was dissolved in water (50 mL) and extracted withMTBE (2×20 mL). The aqueous phase was concentrated under reducedpressure to give 1-ethyl-5-hydroxypiperidin-2-one as a colorless oil.LCMS: RT 0.206 min, m/z=144.2 [M+H]⁺.

1-ethyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one &1-ethyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one

To a solution of 1-ethyl-5-hydroxy-piperidin-2-one (530 mg, 3.70 mmol),3-methyl-4-nitro-1H-pyrazole (706 mg, 5.55 mmol) and PPh, (146 g, 5.55mmol) in THF (20 mL) was added dropwise DIAD (1.12 g, 5.55 mmol) at 0°C. over 20 min. After addition, the mixture was stirred at thistemperature for 40 min, and then the resulting mixture was stirred at20° C. for 11 h. The reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=5:1 to 0:1) to give a mixture of1-ethyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and1-ethyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one as a yellowsolid. LCMS: RT 0.881 min, m/z=253.1 [M+H]⁺.

5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one and5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one

To a solution of1-ethyl-5-(5-methyl-4-nitro-pyrazol-1-yl)piperidin-2-one and1-ethyl-5-(3-methyl-4-nitro-pyrazol-1-yl)piperidin-2-one (420 mg, 1.66mmol) in MeOH (40 mL) was added Pd/C (10%, 176 mg) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 20° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to givea mixture of 5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-oneand 5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one as abrown oil. LCMS: RT 0.566 min, m/z=223.3 [M+H]⁺.

(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,and(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one(A-59, A-60, A-61, and A-62)

To a solution of5-(4-amino-5-methyl-pyrazol-1-yl)-1-ethyl-piperidin-2-one and5-(4-amino-3-methyl-pyrazol-1-yl)-1-ethyl-piperidin-2-one (310 mg, 1.39mmol), and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (370 mg,1.39 mmol) in 1,4-dioxane (10 mL) was added TFA (317 mg, 2.78 mmol). Themixture was stirred at 100° C. for 2 h. The reaction mixture was dilutedwith H₂O (30 mL), adjusted with aq. NaHCO₃ (30 mL) to pH=8 and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give crude product. The crude product was triturated withDMF (5 mL). The undissolved solid was filtered to give crude product asa solid. This crude product was separated by SFC to give5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-oneas a single enantiomer (Peak 1 in SFC) and5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-oneas a single enantiomer (Peak 2 in SFC). The DMF filtrate wasconcentrated to give crude product. This crude product was purified byprep-HPLC (TFA) and then twice of SFC to give5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-oneas a single enantiomer (Peak 1 in SFC) and5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-oneas a single enantiomer (Peak 2 in SFC).

First Eluting Isomer (Peak 1):(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one(A-59)

¹H NMR (400 MHz, MD₃OD): δ ppm 8.25-8.45 (m, 1H), 7.48-7.67 (m, 1H),4.64-4.79 (m, 1H), 3.72-3.84 (m, 1H), 3.56-3.63 (m, 1H), 3.44-3.54 (m,1H), 3.35-3.43 (m, 1H), 2.50-2.61 (m, 2H), 2.32-2.44 (m, 1H), 2.25 (s,3H), 2.09-2.21 (m, 2H), 0.98-1.34 (m, 7H). HPLC: RT 2.480 min. MS: m/z:409.2 [M+H]⁺. SFC: RT 5.72 min, ee=100%.

Second Eluting Isomer (Peak 2):(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one(A-60)

¹H NMR (400 MHz, CD₃OD): δ ppm 8.21-8.48 (m, 1H), 7.43-7.71 (m, 1H),4.67-4.80 (m, 1H), 3.72-3.83 (m, 1H), 3.56-3.62 (m, 1H), 3.44-3.54 (m,1H), 3.34-3.43 (m, 1H), 2.49-2.60 (m, 2H), 2.33-2.44 (m, 1H), 2.25 (s,3H), 2.08-2.21 (m, 2H), 0.97-1.34 (m, 7H). HPLC: RT 2.487 min. MS: m/z:409.1 [M+H]⁺. SFC: RT 6.33 min, ee=100%.

First Eluting Isomer (Peak 1):(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one(A-61)

¹H NMR (400 MHz, CD₃OD): δ ppm 8.34-8.43 (m, 1H), 7.84-7.94 (m, 1H),4.54-4.69 (m, 1H), 3.69-3.79 (m, 2H), 3.38-3.52 (m, 2H), 2.46-2.57 (m,2H), 2.32-2.43 (m, 1H), 2.22-2.30 (m, 1H), 2.19 (s, 4H), 1.18-1.31 (m,2H), 1.07-1.17 (m, 5H). HPLC: RT 2.468 min. MS: m/z: 409.1 [M+H]⁺. SFC:RT 4.87 min, ee=100%.

Second Eluting Isomer (Peak2):5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one(A-62)

¹H NMR (400 MHz, CD₃OD): δ ppm 8.34-8.42 (m, 1H), 7.83-7.95 (m, 1H),4.56-4.71 (m, 1H), 3.68-3.80 (m, 2H), 3.37-3.53 (m, 2H), 2.45-2.58 (m,2H), 2.32-2.43 (m, 1H), 2.23-2.30 (m, 1H), 2.19 (s, 4H), 1.19-1.30 (m,2H), 1.06-1.18 (m, 5H). HPLC: RT 2.464 min. MS: m/z: 409.1 [M+H]⁺. SFC:RT 5.67 min, ee=98.02%.

Example A-44 Synthesis ofN-[5-chloro-1-[[1-(morpholinomethyl)cyclopropyl]methyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-63)N-[5-chloro-1-[[1-(morpholinomethyl)cyclopropyl]methyl]pyrazol-4-yl]-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-63)

To a mixture of5-chloro-1-((1-(morpholinomethyl)cyclopropyl)methyl)-1H-pyrazol-4-amine(70 mg, 258.53 μmol) and4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (75.71mg, 284.38 μmol) in 1,4-dioxane (3 mL) was added TFA (58.96 mg, 517.06μmol) in one portion at 20° C. under N₂. The mixture was stirred at 90°C. for 6 h. The mixture was concentrated under reduced pressure. Theresidue was poured into aq. NaHCO₃ (10 mL) and stirred for 5 min. Theaqueous phase was extracted with EtOAc (3×5 mL). The combined organicphase was washed with brine (10 mL), dried with anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (NH₄HCO₃) to giveN-(5-chloro-1-((1-(morpholinomethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ ppm 8.43 (s, 1H) 7.98 (s, 1H) 6.70 (br. s.,1H) 4.19 (s, 2H) 3.67 (t, J=4.52 Hz, 4H) 2.43 (br. s., 4H) 2.15-2.28 (m,3H) 1.26-1.36 (m, 2H) 1.08-1.20 (m, 2H) 0.68-0.79 (m, 2H) 0.38-0.48 (m,2H). HPLC: RT 2.44 min. MS: [M+H]⁺ m/z: 457.

Example A-45 Synthesis ofN-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(64) andN-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-65)5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-amine

To a mixture of3-(5-chloro-4-nitro-1H-pyrazol-1-yl)-4,4-difluoro-1-(oxetan-3-yl)piperidine(1.1 g, 3.41 mmol) in EtOH (48 mL) and H₂O (12 mL) was added NH₄Cl (911mg, 17.05 mmol) and Fe (951 mg, 17.05 mmol) at 20° C. Then the mixturewas heated to 80° C. and stirred for 2 h. The mixture was cooled to 20°C., filtered and concentrated under reduced pressure. The residue wasadded with water (10 mL) then extracted with EtOAc (3×5 mL). Thecombined organic phase was washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure, togive5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-amineas a red brown solid. LCMS: RT 0.103 min, m/z=293.1 [M+H]⁺.

N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amineandN-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-64 and A-65)

A mixture of5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-amine(200 mg, 683.27 μmol),2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (167 mg, 751.60μmol), Pd₂(dba)₃ (63 mg, 68.33 μmol), XPhos (65 mg, 136.65 μmol) andCs₂CO₃ (534 mg, 1.64 mmol) in 1,4-dioxane (10 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 100° C.for 12 h under N₂. The residue was purified by prep-TLC (SiO₂, PE/Ethylacetate=1/1) to give crude product. The crude was further separated bySFC to provideN-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amineas a single enantiomer (peak 1) andN-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amineas a single enantiomer (peak 2).

First Eluting Isomer (Peak 1):N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-64)

¹H NMR: (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1H), 8.12 (s, 1H), 6.74(bs, 1H), 4.66-4.81 (m, 3H), 4.56-4.64 (m, 2H), 3.64-3.76 (m, 1H),3.04-3.14 (m, 1H), 2.93-3.02 (m, 1H), 2.79-2.89 (m, 1H), 2.10-2.41 (m,4H), 1.24-1.35 (m, 2H), 1.07-1.18 (m, 2H). HPLC: RT 2.914. MS: [M+H]⁺m/z: 479.2. SFC: ee: 99.66%.

Second Eluting Isomer (Peak 2):N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-65)

¹H NMR: (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1H), 8.12 (s, 1H), 6.73(bs, 1H), 4.66-4.82 (m, 3H), 4.54-4.65 (m, 2H), 3.63-3.79 (m, 1H),3.05-3.16 (m, 1H), 2.92-3.03 (m, 1H), 2.78-2.89 (m, 1H), 2.09-2.42 (m,4H), 1.23-1.37 (m, 2H), 1.04-1.20 (m, 2H). HPLC: RT 2.911. MS: [M+H]⁺m/z: 479.1. SFC: ee: 98.9%.

Example A-46 Synthesis of4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-67) 3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one

To a solution of 3-methyl-4-nitro-1H-pyrazole (6.42 g, 50.51 mmol) inDMF (100 mL) was added NaH (2.42 g, 60.61 mmol) at 0° C. under N₂. Themixture was allowed to warmed to 25° C. and stirred for 2 h. Then themixture was cooled to 0° C. and added with 3-bromo-3-methyl-butan-2-one(10 g, 60.61 mmol). The mixture was then stirred at 25° C. for 16 h. Themixture was poured into ice-water (600 mL). The aqueous phase wasextracted with EtOAc (3×200 mL). The combined organic phase was washedwith brine (2×200 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1) to afford3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one as light yellowsolid. LCMS: RT 0.704 min, m/z=212.1 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d): δ 8.30 (s, 1H), 2.56 (s, 3H), 1.98 (s, 3H), 1.74 (s,611).

(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-pyrazol-1-yl)pent-1-en-3-one

A mixture of 3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one (6.2g, 29.35 mmol) and DMF-DMA (34.98 g, 293 mmol, 38.86 mL) was heated to110° C. and stirred for 6 h. The mixture was cooled to 0° C. and yellowsolid was precipitated out. The mixture was filtered to give(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-pyrazol-1-yl)pent-1-en-3-oneas a yellow solid. LCMS: RT 0.691 min, m/z=267.1 [M+H]⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.28 (s, 1H), 7.65 (d, J=12.17 Hz, 1H), 4.55 (d,J=12.30 Hz, 1H), 3.09 (br. s., 3H), 2.72 (br. s., 3H), 2.55 (s, 3H),1.76 (s, 6H).

3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]-4-nitro-pyrazole

To a mixture of(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-pyrazol-1-yl)pent-1-en-3-one(2 g, 7.51 mmol) in AcOH (10 mL) was added hydrazine hydrate (1.88 g,37.55 mmol, 1.83 mL). The mixture was then heated to 100° C. and stirredfor 2 h. The mixture was cooled to 25° C. and concentrated under reducedpressure. The residue was poured into saturated aqueous NaHCO₃ (100 mL).The aqueous phase was extracted with EtOAc (3×50 mL). The combinedorganic phase was washed with brine (100 mL), dried with anhydrousNa₂SO₄, filtered and concentrated to give3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]4-nitro-pyrazole as ayellow solid, which was used for next step directly. LCMS: RT 0.692 min,m/z=236.1 [M+H]⁺.

3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-amine

To a solution of3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]-4-nitro-pyrazole (1.87 g,7.95 mmol) in MeOH (30 mL) was added Pd—C (10%, 0.6 g) under N₂. Thesuspension was degassed under vacuum and purged with H₂ three times. Themixture was stirred under H₂ (15 psi) at 25° C. for 2 h. The reactionmixture was filtered and the filtrate was concentrated to give3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-amine asblack-brown oil. LCMS: RT 0.109 min, m/z=206.1 [M+H]⁺.

4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-67)

To a mixture of4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (100 mg,375 μmol) and3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-amine (77 mg,375.60 μmol) in 1,4-dioxane (2 mL) was added TFA (85 mg, 751 μmol) at25° C. under N₂. The mixture was then heated to 90° C. and stirred for 3h. The mixture was cooled to 25° C. and poured into saturated aqueousNaHCO₃ (30 mL). The aqueous phase was extracted with EtOAc (3×10 mL).The combined organic phase was washed with brine (10 mL), dried withanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by prep-HPLC (neutral) to afford4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl³): δ 8.39 (br. s., 1H), 7.83 (br. s., 1H), 7.51(br. s., 1H), 6.80 (br. s., 1H), 6.19 (br. s., 1H), 2.28 (s, 3H), 2.20(br. s., 1H), 2.00 (s, 6H), 1.19 (d, J=9.70 Hz, 2H), 1.05-1.13 (m, 2H).HPLC: RT 2.589 min. MS: [M+H]⁺ m/z: 392.2.

Example A-47 Synthesis of4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-69) and4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-70) and4-cyclopropyl-N-(5-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-68) 1-(cyclopent-3-en-1-yl)-5-methyl-4-nitro-1H-pyrazole and1-(cyclopent-3-en-1-yl)-3-methyl-4-nitro-1H-pyrazole

To a solution of 3-methyl-4-nitro-1H-pyrazole (20 g, 157.36 mmol),cyclopent-3-en-1-ol (15.88 g, 188.83 mmol) and PPh, (61.91 g, 236.04mmol) in THF (300 mL) was added DIAD (47.73 g, 236.04 mmol) at 0° C. Themixture was stirred at 25° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure to give a residue, which waspurified by silica gel chromatography (PE:EtOAc=50:1 to 20:1) to give amixture of 1-(cyclopent-3-en-1-yl)-5-methyl-4-nitro-1H-pyrazole and1-(cyclopent-3-en-1-yl)-3-methyl-4-nitro-1H-pyrazole as a yellow oil.LCMS: RT 1.301 min, m/z=194.1 [M+H]⁺.

Ethyl3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylateand ethyl3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylate

To a mixture of I-cyclopent-3-en-1-yl-5-methyl-4-nitro-pyrazole and1-cyclopent-3-en-1-yl-3-methyl-4-nitro-pyrazole (10 g, 51.76 mmol), bis[(Z)-1-methyl-3-oxo-but-1-enoxy]copper (948 mg, 3.62 mmol) in DCE (300mL) was added a solution of ethyl 2-diazoacetate (23.6 g, 207.04 mmol)in DCE (600 mL) over a period of 12 h at 90° C. The mixture was stirredat 90° C. for 4 h. The reaction mixture was concentrated under reducedpressure to give a residue, which was purified by silica gel columnchromatography (PE:EtOAc=20:1 to 5:1) to give a mixture of ethyl3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylateand ethyl3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylateas a yellow solid. LCMS: RT 0.831 min, m/z=280.1 [M+H]⁺.

3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylicacid and3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylicacid

To a mixture of ethyl3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylate (4)and ethyl3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylate(4A) (2.6 g, 9.31 mmol) in THF (40 mL) and H₂O (10 mL) was addedLiOH.H₂O (781 mg, 18.62 mmol). The mixture was stirred at 25° C. for 12h. The reaction mixture was poured into H₂O (30 mL) and extracted withMTBE (20 mL×2), the aqueous layer was separated and adjusted to pH=3 by1 N HCl, then it was extracted with EtOAc (2×30 mL), dried over Na₂SO₄,concentrated under reduced pressure to give a mixture of3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylicacid and3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylicacid as a white solid. LCMS: RT 1.072 min, m/z=252.1 [M+H]⁺.

3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamideand3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide

To a mixture of3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylic acidand 3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylicacid (800 mg, 3.18 mmol) in DCM (20 mL) was added DMF (200 μL) and(COCl)₂ (807 mg, 6.36 mmol) drop-wise at 0° C. over a period of 10 minunder N₂. The reaction mixture was then stirred at 25° C. for 1 h,concentrated under reduced pressure to give a residue. Then the residuewas dissolved in THF (20 mL) and added dropwise to NH₃.H₂O (7.8 g, 222.6mmol) at 25° C. The resulting mixture was stirred at 25° C. for 3 h. Thereaction mixture was concentrated under reduced pressure and extractedwith EtOAc (50 mL 2). The combined organic phase was washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a mixture of3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamideand3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide.LCMS: RT 1.158 min, m/z=251.1 [M+H]⁺.

(E)-N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamideand(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide

A mixture of3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide and3-(3-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide (800mg, 3.2 mmol) in DMF-DMA (3.81 g, 32 mmol) was heated to 95° C. andstirred for 2 h. The mixture was cooled to 25° C., concentrated underreduced pressure to give a residue, which was slurried with MTBE (10mL), filtered to give pure(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide(0.6 g) as a white solid. The filtrate was concentrated under reducedpressure to give a mixture of(E)-N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamideand(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide.LCMS: RT 1.16 min, m/z=306.1 [M+H]⁺.

3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazole

To a solution of(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide(800 mg, 2.62 mmol) in AcOH (8 mL) was added NH₂NH₂.H₂O (1.97 g, 39.3mmol). The mixture was stirred at 95° C. for 2 h. The reaction mixturewas concentrated under reduced pressure and poured into ice-water (20mL), adjusted to pH=9 with aq. NaHCO₃, and extracted with EtOAc (50mL×2). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure, to give3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazole.LCMS: RT 0.633 min, m/z=275.1 [M+H]⁺.

1-methyl-3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazoleand1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazole

To a solution of3-[3-(3-methyl-4-nitro-pyrazol-1-yl)-6-bicyclo[3.1.0]hexanyl]-1H-1,2,4-triazole(8) (400 mg, 1.46 mmol) in MeCN (20 mL) was added Mel (248 mg, 1.75mmol) and Cs₂CO₃ (476 mg, 1.46 mmol). The mixture was stirred at 50° C.for 12 h. The reaction mixture was filtered and concentrated underreduced pressure to give a residue, which was purified by prep-TLC(SiO₂, DCM:MeOH=10:1) to give a mixture of1-methyl-3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazoleand1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazole.LCMS: RT 0.677 min, m/z=289.1 [M+H]⁺.

3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amineand3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amine

A mixture of1-methyl-3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazoleand1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazole(300 mg, 1.04 mmol), NH₄Cl (278 mg, 5.2 mmol) and Fe (290 mg, 5.2 mmol)in EtOH (25 mL) and H₂O (5 mL) was stirred at 90° C. for 2 h. It wasfiltered and the filtrate was concentrated under reduced pressure togive a residue, which was slurried with DCM:MeOH (V:V, 10:1, 15 mL),filtered and the filtrate was concentrated under reduced pressure togive a mixture of3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amineand3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amine.LCMS: RT 0.369 min, m/z=259.2 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-69) and4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-70)

A mixture of3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amineand3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amine(200 mg, 774.23 μmol),4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (247 mg,929 μmol) and TFA (177 mg, 1.55 mmol) in 1,4-dioxane (30 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 95° C. for 4 h under N₂. It was poured into H₂O (15 mL),adjusted to pH=8 with aq.NaHCO₃, extracted with EtOAc (30 mL×2). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to get a residue, which was purified by prep-HPLC(neutral) to give4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(69) and4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(70).

4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-69)

¹H NMR (400 MHz, CDCl₃): δ 8.41 (d, J=18.96 Hz, 1H), 7.76-7.91 (m, 2H),6.55-6.71 (m, 1H), 4.30-4.45 (m, 1H), 3.85 (s, 3H), 2.33-2.59 (m, 4H),2.15-2.29 (m, 4H), 1.96-2.04 (m, 3H), 1.22-1.30 (m, 2H), 1.05-1.17 (m,2H). HPLC: RT 2.96 min. MS: [M+H]⁺=m/z: 445.2.

4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-70)

¹H NMR (400 MHz, CDCl₃): δ 8.43 (br. s., 1H), 7.74-7.93 (m, 1H), 7.71(s, 1H), 6.58-6.81 (m, 1H), 4.41 (t, J=8.16 Hz, 1H), 3.90 (s, 3H),2.36-2.60 (m, 4H), 2.25 (s, 3H), 2.05-2.21 (m, 3H), 1.77 (br. s., 1H),1.27 (br. s., 2H), 1.04-1.19 (m, 2H). HPLC: RT 2.60 min. MS: [M+H]⁺ m/z:445.2.

1-methyl-5-(3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazoleand1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazole

To a mixture of(E)-N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamideand(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide(200 mg, crude) in AcOH (8 mL) was added methylhydrazine (1.32 g, 11.50mmol). The mixture was stirred at 95° C. for 2 h. The reaction mixturewas concentrated under reduced pressure and poured into ice-water (20mL), adjusted to pH=9 with aq. NaHCO₃, and extracted with EtOAc (50mL×2). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give amixture of1-methyl-5-(3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazoleand1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-v)-1H-1,2,4-triazoleas yellow oil. LCMS: RT 0.950 min, m/z=289.1 [M+H]⁺.

5-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amineand3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amine

A mixture of1-methyl-5-(3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazoleand1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4-triazole(0.2 g, crude), NH₄Cl (195 mg, 3.64 mmol) and Fe (203 mg, 3.64 mmol) inEtOH (25 mL) and H₂O (5 mL) was stirred at 90° C. for 2 h. It wasfiltered and the filtrate was concentrated under reduced pressure togive a residue, which was slurry with DCM:MeOH (V:V, 10:1, 15 mL),filtered and the filtrate was concentrated under reduced pressure togive a mixture of5-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amineand3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amineas a yellow oil. LCMS: RT 0.320 min, m/z=259.2 [M+H]⁺.

4-cyclopropyl-N-(5-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-68)

A mixture of5-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amineand3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-amine(188 mg, crude),4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (235 mg,883 μmol) and TFA (168 mg, 1.47 mmol) in 1,4-dioxane (30 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 95° C. for 4 h under N₂. It was poured into H₂O (15 mL),adjusted to pH=8 with aq.NaHCO₃, extracted with EtOAc (30 mL×2). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to get a residue, which was purified by prep-HPLC(neutral) and then it was separated by SFC to give4-cyclopropyl-N-(5-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(68). ¹H NMR (400 MHz, CDCl₃): δ 8.38 (s, 1H), 7.55-7.74 (m, 2H),6.44-6.70 (m, 1H), 4.37 (br. s., 1H), 3.92 (s, 3H), 2.66 (br. s., 2H),2.40 (dd, J=13.16, 7.89 Hz, 2H), 2.21 (s, 3H), 2.16 (br. s., 2H), 1.73(br. s., 1H), 1.19-1.25 (m, 2H), 1.08 (d, J=4.38 Hz, 2H). HPLC: RT 2.86min. MS: [M+H]⁺ m/z: 445.2.

Example A-48 Synthesis ofN-(1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-71)1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine

To a solution of4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole(100 mg, 0.42 mmol) in EtOH (2 mL) and water (0.5 mL) was added NH₄Cl(68 mg, 1.27 mmol) and Fe (71 mg, 1.27 mmol), then the mixture wasstirred at 100° C. for 1 h. The reaction mixture was concentrated underreduced pressure, then diluted with EtOAc (5 mL×2) and filtered. Thefiltrate was concentrated under reduced pressure to give1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine asa brown solid. LCMS: RT 0.11 min, m/z=207.2 [M+H]⁺.

N-(1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine(A-71)

To a solution of1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine (40mg, 0.19 mmol) in 1,4-dioxane (2 mL) was added4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (57 mg,0.21 mmol) and TFA (44 mg, 0.029 mL, 0.39 mmol). Then the mixture wasstirred at 100° C. for 1 h. The mixture was concentrated under reducedpressure to give a residue, which was purified by prep-HPLC (neutral) togiveN-(1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR 400 MHz, CHLOROFORM-d): δ 8.40 (br. s., 1H), 7.90 (br. s., 1H),7.47 (br. s., 1H), 6.88 (br. s., 1H), 2.27 (s, 3H), 2.21 (br. s., 1H),2.03 (s, 6H), 1.19 (br. s., 2H), 1.11 (d, J=7.6 Hz, 2H). HPLC: RetentionTime: 2.81 min. MS: [M+H]⁺ m/z: 393.1.

Example A-49 Synthesis of4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-72) and4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-73)1-(difluoromethyl)-3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,2,4-triazoleand1-(difluoromethyl)-5-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,2,4-triazole

To a mixture of3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1H-1,2,4-triazole (5g, 21.17 mmol) in DMF (50 mL) was added K₂CO₃ (8.78 g, 63.51 mmol) at20° C. The mixture was heated to 90° C. then chloro(difluoro)methane wasbubbled into the mixture at 90° C. for 1 h. The mixture was cooled to20° C. and poured into ice-water (300 mL). The aqueous phase wasextracted with EtOAc (3×100 mL). The combined organics were washed withbrine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1 to 0:1) to give1-(difluoromethyl)-3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,2,4-triazoleas a yellow oil and1-(difluoromethyl)-5-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,2,4-triazoleas a yellow oil. LCMS: RT 0.735 min, m/z=287.2 [M+H]⁺.

1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine

To a mixture of1-(difluoromethyl)-3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,2,4-triazole(2.37 g, 8.28 mmol) in EtOH (96 mL) and H₂O (24 mL) was added NH₄Cl(2.21 g, 41.40 mmol) and Fe (2.31 g, 41.40 mmol) at 20° C. The mixturewas heated to 80° C. and stirred for 1 h. The mixture was cooled to 20°C. and concentrated under reduced pressure. The residue was added withwater (30 mL). The aqueous phase was extracted with EtOAc (3-10 mL),washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amineas a brown oil. LCMS: RT 1.012 min, m/z=257.2 [M+H]⁺.

4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine(100 mg, 390.24 μmol) and4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (86 mg,325.20 μmol) in 1,4-dioxane (1 mL) was added TFA (74 mg, 650.40 μmol,48.16 μL) at 20° C. The mixture was heated to 90° C. and stirred for 2h. The mixture was cooled to 20° C. and adjusted pH=7-8 by adding aq.NaHCO₃. The aqueous phase was extracted with EtOAc (3×5 mL), washed withbrine (5 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by prep-HPLC (neutral)to give4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas a brown solid. LCMS: RT 0.855 min, m/z=443.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.45 (br. s., 1H), 8.40 (br. s., 1H), 7.97 (br. s., 1H),7.04-7.42 (m, 2H), 6.73 (br. s., 1H), 2.25 (s, 4H), 2.06 (s, 6H),1.18-1.29 (m, 2H), 1.03-1.16 (m, 2H). HPLC: RT 2.871 min. MS: [M+H]⁺m/z: 443.1.

1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine

To a mixture of1-(difluoromethyl)-5-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,2,4-triazole(1.97 g, 6.88 mmol) in EtOH (48 mL) and H₂O (12 mL) was added NH₄Cl(1.84 g, 34.41 mmol) and Fe (1.92 g, 34.41 mmol) at 20° C. The mixturewas heated to 80° C. and stirred for 1 h. The mixture was cooled to 20°C. and concentrated under reduced pressure. The residue was added withwater (20 mL) and extracted with EtOAc (3×8 mL). The combined organicphase was washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amineas a brown solid. LCMS: RT 0.924 min, m/z=257.2 [M+H]⁺.

4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-73)

To a mixture of1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine(100 mg, 390.24 μmol) and4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (86 mg,325.20 μmol) in 1,4-dioxane (1 mL) was added TFA (74 mg, 650.40 μmol,48.16 L) at 20° C. The mixture was heated to 90° C. and stirred for 2 h.The mixture was cooled to 20° C. and adjusted pH=7-8 by adding sat. aq.NaHCO₃ then was extracted with EtOAc (3×5 mL), washed with brine (5 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (neutral) to give4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.LCMS: RT 0.829 min, m/z=443.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ ppm 8.45(s, 1H), 8.43 (br. s., 1H), 8.01 (br. s., 1H), 6.76 (br. s., 1H),6.19-6.54 (m, 1H), 2.20-2.30 (m, 4H), 2.05-2.15 (m, 6H), 1.14 (d, J=7.53Hz, 4H). HPLC: RT 2.671 min. MS: [M+H]⁺ m/z: 443.2.

Example A-50 Synthesis of4-cyclopropyl-N-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-74)N′-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanehydrazide

To a solution of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoicacid (2 g, 9.38 mmol) in DCM (80 mL) was added acetohydrazide (834 mg,11.3 mmol), HATU (7.13 g, 18.8 mmol) and DIPEA (2.4 g, 3.3 mL, 18.8mmol). The reaction mixture was stirred at 20° C. for 1 h. The mixturewas concentrated under reduced pressure to give a residue, which waspurified by silica gel column chromatography (PE:EtOAc=10:1 to EtOAc) togiveN′-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanchydrazideas a yellow oil. LCMS: RT 0.627 min, m/z=270.2 [M+H]⁺.

2-(4-((4-cyclopropyl-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo2-methyl-5-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1,3,4-oxadiazole

A solution ofN′-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanchydrazide(200 mg, 0.74 mmol) in POCl₃ (0 mL) was stirred at 100° C. for 2 h. Thereaction mixture was poured into ice-water (2 mL), and extracted withEtOAc (3×2 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to give a residue, which waspurified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give2-(4-((4-cyclopropyl-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo2-methyl-5-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1,3,4-oxadiazoleas a white solid. LCMS: RT 0.662 min, m/z=252.2 [M+H]⁺.

3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-amine

To a solution of Pd/C (80 mg) in MeOH (20 mL) was added2-methyl-5-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1,3,4-oxadiazole(170 mg, 0.68 mmol), then the mixture was stirred at 20° C. for 2 hunder H₂ (15 psi). The reaction mixture was concentrated under reducedpressure to give residue, which was diluted with EtOAc (3×20 mL). Thefiltrate was concentrated under reduced pressure to give3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-amineas a yellow solid. LCMS: RT 0.102 min, m/z=222.2 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-74)

To a solution of3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-amine(130 mg, 0.59 mmol) in 1,4-dioxane (3 mL) was added4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (157 mg,0.59 mmol) and TFA (67 mg, 0.04 mL, 0.59 mmol). Then the mixture wasstirred at 80° C. for 2 h. The mixture was concentrated under reducedpressure to give a residue, which was purified by prep-HPLC (neutral) togive4-cyclopropyl-N-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CHLOROFORM-d): δ8.42 (br. s., 1H), 7.96 (br. s., 1H),6.67 (br. s., 1H), 2.51 (s, 3H), 2.24 (s, 3H), 2.20-2.24 (m, 1H), 2.07(s, 6H), 1.23 (br. s., 2H), 1.14 (br. s., 2H). HPLC: RT 3.10 min. MS:[M+H]⁺ m/z: 408.2.

Example A-51 Synthesis of(R)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand(S)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-78 and A-79)(R)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand(S)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-78 and A-79)

To a solution of1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-amine(200 mg, 984.06 μmol) and1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amineand 4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (262mg, 984.06 μmol) in 1,4-dioxane (5 mL) was added TFA (56 mg, 492.03μmol). The mixture was stirred at 100° C. for 1 h. The reaction mixturewas diluted with H₂O (20 mL), and adjusted with aq. NaHCO₃ (10 mL) topH=8 and extracted with EtOAc (3×10 mL). The combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (neutral) to give 70 mg mixture of product, whichwas purified by SFC to give(R)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(peak 1 in SFC, stereochemistry randomly assigned), and(S)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(peak 2 in SFC, stereochemistry randomly assigned).

First Eluting Isomer (Peak 1):4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-78)

¹H NMR (400 MHz, CD₃OD): δ ppm 8.40 (s, 1H), 7.60-8.05 (m, 1H),7.23-7.34 (m, 1H), 7.10-7.22 (m, 1H), 5.73-5.85 (m, 1H), 4.27-4.44 (m,1H), 4.11-4.25 (m, 1H), 3.18-3.31 (m, 1H), 2.76-2.93 (m, 1H), 2.20 (br.s., 4H), 1.01-1.39 (m, 4H). HPLC: RT 2.373 min. MS: me: 390.2 [M+H]⁺.SFC: RT 2.52 min.

Second Eluting Isomer (Peak 2):4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-79)

¹H NMR (400 MHz, CD₃OD): δ ppm 8.41 (s, 1H), 7.69-8.07 (m, 1H),7.29-7.41 (m, 1H), 7.18-7.27 (m, 1H), 5.77-5.93 (m, 1H), 4.31-4.49 (m,1H), 4.14-4.28 (m, 1H), 3.21-3.30 (m, 1H), 2.77-2.93 (m, 1H), 2.20 (br.s., 4H), 1.03-1.38 (m, 4H). HPLC: RT 2.369 min. MS: m/z: 390.1 [M+H]⁺SFC: RT 2.58 min.

Example A-52 Synthesis of4-cyclopropyl-N-(1-(difluoro(1-methyl-1H-1,2,4-triazol-3-yl)methyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-77),4-cyclopropyl-N-[1-[difluoro(1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-75) and4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-76)N′-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanehydrazide

To a solution of tert-butylN-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]carbamate(653 mg, 2.25 mmol) and4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (599 mg,2.25 mmol) in 1,4-dioxane (10 mL) was added p-TsOH (387 mg, 2.25 mmol).The mixture was stirred at 100° C. for 10 h. The reaction solution wasconcentrated under reduced pressure. The residue was added with water(20 mL), adjusted to pH=7 with aq.NaHCO₃. The aqueous phase wasextracted with EtOAc (3×10 mL). The organic layers were combined, washedwith brine (5 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2,2-difluoro-acetamideas a yellow solid. LCMS: RT 0.822 min, m/z=377.1 [M+H]⁺.

2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-N-(dimethylaminomethylene)-2,2-difluoro-acetamide

A mixture of2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2,2-difluoro-acetamide(720 mg, 1.91 mmol), DMF-DMA (3.25 g, 27.27 mmol, 3.61 mL) was degassedand purged with N₂ for 3 times, and then the mixture was stirred at10˜30° C. for 12 h under N₂. The reaction mixture was concentrated underreduced pressure to give2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-N-(dimethylaminomethylene)-2,2-difluoro-acetamideas a yellow oil. LCMS: RT 0.807 min, m/z=432.1 [M+H]⁺.

4-cyclopropyl-N-(1-(difluoro(1H-1,2,4-triazol-3-yl)methyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-77)

To a solution of(NE)-2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-N-(dimethylaminomethylene)-2,2-difluoro-acetamide(200 mg, 463.65 μmol) in AcOH (2 mL) was added NH₂NH₂.H₂O (23 mg, 463.65μmol, 22.53 μL). The mixture was stirred at 15° C. for 2 h. The reactionsolution was poured into ice-water (5 mL), adjusted to pH=7 with aq.NaHCO₃, extracted with EtOAc (3×5 mL). The organic layers were combined,washed with brine (5 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by prep-HPLC(FA) togive4-cyclopropyl-N-[1-[difluoro(1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR 400 MHz, CHLOROFORM-d): δ 8.40 (s., 1H), 8.28 (s., 2H), 6.51-6.97(br, 1H), 2.21 (s, 4H), 1.17-1.26 (m, 2H), 1.09 (m, 2H). HPLC: RT 2.76min. MS: (M+H⁺) m/z: 401.1

4-cyclopropyl-N-[1-[difluoro(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-75 and A-76)

To a solution of4-cyclopropyl-N-[1-[difluoro(1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(500 mg, 1.25 mmol, crude) in MeCN (10 mL) was added Mel (532 mg, 3.75mmol, 233.27 μL) and K₂CO₃ (518 mg, 3.75 mmol). The mixture was stirredat 15° C. for 10 h. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (FA) to give4-cyclopropyl-N-[1-[difluoro-(1-methyl-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.

4-cyclopropyl-N-[1-[difluoro(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-75)

¹H NMR (400 MHz, CHLOROFORM-d): δ8.46 (s., 1H), 8.29 (s., 1H), 8.17 (s,1H), 6.89 (br. s., 1H), 4.04 (s, 3H), 2.16-2.33 (m, 4H), 1.24-1.32 (m,2H), 1.15 (m, 2H). HPLC: RT 3.23 min. MS: [M+H]⁺ m/z: 415.1.

4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-76)

¹H NMR (400 MHz, CHLOROFORM-d): δ8.49 (s., 1H), 8.25-8.43 (m, 1H), 7.99(s, 1H), 6.79 (br. s., 1H), 4.02 (s, 3H), 2.17-2.33 (m, 4H), 1.29 (m,2H), 1.19 (m, 2H). HPLC: RT 3.47 min. MS: [M+H]⁺ m/z: 415.1.

Example A-53 Synthesis of4-cyclopropyl-N-(5-methyl-1-((1R,3S)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-(3-methyl-1-((1R,3S)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-80 and A-81)3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide and3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide

To a mixture of 3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylicacid and 3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylic acid (Ig, 4.44 mmol) in DCM (15 mL) was added a solution of oxalyl chloride(1.13 g, 8.88 mmol, 777.34 μL) and DMF (162.26 mg, 2.22 mmol) dropwiseat 0° C. and stirred at 15° C. for 1 h. The reaction mixture wasconcentrated to get a residue. A mixture of the residue in THF (10 mL)was added to NH₃.H₂O (20 mL) and stirred at 15° C. for 1 h. The mixturewas concentrated to get3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide and3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide (1.2 g,crude). LCMS: RT 0.53 min, m/z=225.2 [M+H]⁺.

N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamideandN-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide

A solution of 3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamideand 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide (500 mg,2.23 mmol) in DMF-DMA (5 mL) was stirred at 80° C. for 2 h. The reactionmixture was concentrated under reduced pressure to getN-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamideandN-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamideas a yellow gum. LCMS: RT 0.548 mn, m/z=280.2 [M+H]⁺.

1-methyl-5-((1r,3r)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,2,4-triazoleand1-methyl-5-((1r,3r)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,2,4-triazole

To a solution ofN-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamideandN-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide(620 mg, 2.23 mmol) in CH—COOH (6 mL) was added methylhydrazine (2.57 g,22.30 mmol, 2.92 mL, 40% purity). The mixture was stirred at 90° C. for2 h. The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with water (60 mL), adjust to pH=8 by aq. NaHCO₃,and extracted with EtOAc (3×30 mL). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byprep-TLC (SiO₂, DCM:MeOH=20:1), to give1-methyl-5-((1r,3r)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,2,4-triazoleand1-methyl-5-((1r,3r)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,2,4-triazole.LCMS: RT 0.881 mn, m/z=263.1[M+H]⁺.

5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-amine

To a solution of1-methyl-5-((1r,3r)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,2,4-triazole(40 mg, 152.51 μmol) in MeOH (4 mL) was added Pd—C (10%, 0.02 g) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 15° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to give5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-amineas a yellow solid. LCMS: RT 0.173 mn, m/z=233.1[M+H]⁺.

3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-amine

To a solution of1-methyl-5-((1r,3r)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,2,4-triazole(60 mg, 228.78 μmol) in EtOH (2 mL) and H₂O (0.5 mL) was added Fe (64mg, 1.14 mmol) and NH₄Cl (61 mg, 1.14 mmol). The mixture was stirred at80° C. for 2 h. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was added with EtOAc and filtered. Thefiltrate was concentrated to give3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-amineas a yellow gum.

4-cyclopropyl-N-(5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-80)

A mixture of5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-amine(35 mg, 150.68 μmol),4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (32 mg,120.54 μmol) and TsOH.H₂O (29 mg, 150.68 μmol) in 1,4-dioxane (3 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 90° C. for 6 h under N₂. The residue was diluted with H₂O (20mL), adjusted to pH=8 by aq. NaHCO₃ and then extracted with EtOAc (3×10mL). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-HPLC (FA) to give4-cyclopropyl-N-(5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₃): δ 8.38 (s, 1H), 7.87 (s, 1H), 7.74 (br. s.,1H), 5.11 (t, J=7.59 Hz, 1H), 3.81 (s, 3H), 3.76 (dt, J=9.47, 4.67 Hz,1H), 3.22 (q, J=9.62 Hz, 2H), 2.85 (t, J=8.47 Hz, 2H), 2.19 (s, 4H) 1.25(d, J=2.51 Hz, 2H), 1.09 (dd, J=7.59, 3.20 Hz, 2H). HPLC: RT: 3.06 min.MS: m/z: 419.2 [M+H]⁺.

4-cyclopropyl-N-(3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(A-81)

A mixture of3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-amine(50 mg, 215.25 μmol),4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (46 mg,172.20 μmol), TsOH.H₂O (61 mg, 322.88 μmol) in ethylene glycolmonomethyl ether (2 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 110° C. for 5 h under N₂. The reactionmixture was concentrated under reduced pressure. The residue was dilutedwith H₂O (20 mL), adjusted to pH=8 by aq. NaHCO₃ and then extracted withEtOAc (3×10 mL). The combined organic layers were washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue, which was purified by prep-HPLC (FA) to give4-cyclopropyl-N-(3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.¹H NMR (400 MHz, CDCl₁): S 8.42 (br. s., 1H), 7.86 (s, 1H), 7.80 (br.s., 1H), 5.07 (t, J=7.72 Hz, 1H), 3.81 (s, 3H), 3.73 (dt, J=9.22, 4.80Hz, 1H), 3.11-3.20 (m, 2H), 2.87 (br. s., 2H), 2.30 (s, 3H), 2.23 (br.s., 1H), 1.23-1.30 (m, 2H), 1.06-1.19 (m, 2H). HPLC: RT: 2.90 min. MS:m/z: 419.1 [M+H]⁺.

Example A-54 Synthesis of4-cyclopropyl-N-[1-[(7R)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[(7S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-82 and A-83) 3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidin-2-one

To a solution of 3-methyl-4-nitro-1H-pyrazole (4.15 g, 32.64 mmol),3-hydroxypyrrolidin-2-one (3 g, 29.67 mmol) and PPh3 (11.67 g, 44.51mmol) in THF (100 mL) was added DIAD (9 g, 44.51 mmol) at 0° C. underN2. The mixture was stirred at 25° C. for 6 h. The mixture was filteredand filtrate was concentrated to give a residue. The residue waspurified by silica gel column chromatography (PE:EtOAc=1:1) to give acrude product, which was triturated with MTBE (20 mL), to give3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidin-2-one as a white solid.LCMS: RT 0.226 min, m/z=211.2 [M+H]+, 0.1H NMR (400 MHz, DMSO-d6): δ8.89 (s, 1H), 8.25 (br. s., 1H), 5.09 (t, J=9.10 Hz, 1H), 3.27-3.42 (m,3H), 2.53-2.60 (m, 2H), 2.43 (s, 3H).

3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidine-2-thione

To a mixture of 3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidin-2-one (1.1g, 5.23 mmol) in toluene (20 mL) was added Lawesson's reagent (1.06 g,2.62 mmol). The mixture was then heated to 110° C. and stirred for 2 h.The mixture was concentrated under reduced pressure to give a residue.The residue was added with EtOAc (10 mL) and filtered. The filtrate wasconcentrated to afford3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidine-2-thione as a white solid.LCMS: RT 0.458 min, m/z=227.1 [M+H]⁺, 1H NMR (400 MHz, DMSO-d6): δ 10.75(br. s., 1H), 8.92 (s, 1H), 5.33 (t, J=8.60 Hz, 1H), 3.59-3.72 (m, 2H),2.59-2.69 (m, 3H), 2.43 (s, 3H).

3-methyl-1-(5-methylsulfanyl-3,4-dihydro-2H-pyrrol-4-yl)-4-nitro-pyrazole

To a mixture of 3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidine-2-thione(1.07 g, 4.73 mmol) and K2CO3 (3.27 g, 23.65 mmol) in THF (20 mL) wasadded CH₃I (3.36 g, 23.65 mmol, 1.47 mL). The mixture was then stirredat 25° C. for 16 h. The reaction mixture was filtered and the filtratewas concentrated to give3-methyl-1-(5-methylsulfanyl-3,4-dihydo-2H-pyrrol-4-yl)-4-nitro-pyrazole)as a white solid. LCMS: RT 0.839 min, m/z=241.1 [M+H]⁺.

7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

To a solution of3-methyl-1-(5-methylsulfanyl-3,4-dihydro-2H-pyrrol-4-yl)-4-nitro-pyrazole(800 mg, 3.33 mmol) in HCOOH (2 mL) and triethoxymethane (2 mL) wasadded formohydrazide (199 mg, 3.33 mmol) at 25° C. under N2. The mixturewas then heated to 150° C. and stirred for 2 h. The mixture was cooledto 25° C. and concentrated under reduced pressure. The residue waspoured into ice-water (100 mL). The aqueous phase was extracted withEtOAc (3×50 mL). The combined organic phase was washed with brine (50mL), dried with anhydrous Na2SO₄, filtered and concentrated. The residuewas purified by prep-TLC (SiO2, CH2C12:MeOH=10:1) to afford7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazoleas a yellow solid. LCMS: RT 0.218 min, m/z=235.1 [M+H]+. 1H NMR (400MHz. DMSO-d6): δ 9.03 (s, 1H), 8.56 (s, 1H), 6.03 (dd, J=3.97, 8.38 Hz,1H), 4.27 (ddd, J=6.40, 7.94, 10.81 Hz, 1H), 4.15 (ddd, J=4.41, 8.38,11.03 Hz, 1H), 3.24-3.30 (m, 1H), 2.86-2.95 (m, 1H), 2.39 (s, 3H).

1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)-3-methyl-pyrazol-4-amine

To a solution of7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(123 mg, 525.17 μmol) in MeOH (10 mL) was added Pd—C (10%, 20 mg) underN2. The suspension was degassed under vacuum and purged with H2 threetimes. The mixture was stirred under H2 (15 psi) at 25° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated toafford1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)-3-methyl-pyrazol-4-amineas a yellow gum. LCMS: RT 0.085 min, m/z=205.1 [M+H]+.

4-cyclopropyl-N-[1-[(7R)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[(7S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine(A-82 and A-83)

To a mixture of1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)-3-methyl-pyrazol-4-amine(81 mg, 396.61 μmol) and4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (105 mg,396.61 μmol) in ethylene glycol monomethyl ether (2 mL) was added TFA (4mg, 39.66 μmol). The mixture was then heated to 100° C. and stirred for2 h. The mixture was cooled to 25° C. and poured into saturated aqueousNaHCO₃ (30 mL). The aqueous phase was extracted with EtOAc (3×10 mL).The combined organic phase was washed with brine (10 mL), dried withanhydrous Na2SO₄, filtered and concentrated to give a residue. Theresidue was purified by prep-HPLC (neutral) and further separated by SFCto afford4-cyclopropyl-N-[1-[(7R)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amineand4-cyclopropyl-N-[1-[(7S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.

First Eluting Isomer (A-83)

1H NMR (400 MHz, CDCl3): δ 8.40 (br. s., 1H), 8.22 (s, 1H), 7.91 (br.s., 1H), 6.59-6.94 (m, 1H), 5.64-5.75 (m, 1H), 4.34-4.46 (m, 1H),4.12-4.23 (m, 1H), 3.18-3.38 (m, 2H), 2.19 (s, 4H), 1.23 (br. s., 2H),1.13 (d, J=6.17 Hz, 2H). HPLC: RT 2.45 min. MS: [M+H]+ m/z: 391.1. SFC:RT 2.46 min.

Second Eluting Isomer (A-82)

1H NMR (400 MHz, CDCl3): δ 8.38 (d, J=5.73 Hz, 1H), 8.20 (d, J=6.62 Hz,1H), 7.87 (br. s., 1H), 6.74-7.12 (m, 1H), 5.66 (br. s., 1H), 4.37 (br.s., 1H), 4.15 (br. s., 1H), 3.11-3.40 (m, 2H), 1.97-2.34 (m, 4H), 1.19(br. s., 2H), 1.09 (br. s., 2H). HPLC: RT 2.46 min. MS: [M+H]+ m/z:391.1. SFC: RT 3.78 min.

Example A-55

The following compounds were made according to similar proceduresdescribed above. The LCMS conditions used to isolate the compounds areas provided above in the general method.

MS No. [M + H]⁺ A-84 390.2 A-85 367.1 A-86 367.1 A-87 377.1 A-88 367.1A-89 390.2 A-90 390.2 A-91 367.1 A-92 390.2 A-93 381.2 A-94 381.1 A-95381.2 A-96 405.2 A-97 405.2

B: Compound Preparation

In the following Examples, all non-aqueous reactions were carried out inoven-dried or flame-dried glassware under nitrogen atmosphere. Allchemicals were purchased from commercial vendors and used as is, unlessotherwise specified. Reactions were magnetically stirred and monitoredby thin layer chromatography (TLC) with 250 μm pre-coated silica gelplates, visualized either with UV, or in an iodine chamber. Flash columnchromatography was performed using silica gel (100-200 mesh). Chemicalshifts are reported relative to chloroform (δ 7.26), methanol (S 3.31),or DMSO (S 2.50) for ¹H NMR HPLC analysis was performed on Shimadzu 20ABHPLC system with a photodiode array detector and Luna-C18(2) 2.0×50 mm,5 μm column at a flow rate of 1.2 mL/min with a gradient solvent Mobilephase A (MPA, H₂O+0.037% (v/v) TFA): Mobile phase B (MPB, ACN+0.018%(v/v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92min, 10% MPB: 5.5 min, 10% MPB). LCMS was detected under 220 and 254 nmor used evaporative light scattering (ELSD) detection as well aspositive electrospray ionization (MS). Semi-preparative HPLC wasperformed by either acidic or neutral condition. Acidic: Luna C18 100×30mm, 5 μm; MPA: HCl/H₂O=0.04%, or formic acid/H₂O=0.2% (v/v); MPB: ACN.Neutral: Waters Xbridge 150×25, 5 μm; MPA: 10 mM NH₄HCO₃ in H₂O; MPB:ACN. Gradient for both conditions: 10% of MPB to 80% of MPB within 12min at a flow rate of 20 mL/min, then 100% MPB over 2 min, 10% MPB over2 min, UV detector. SFC analysis was performed on Thar analytical SFCsystem with a UV/Vis detector and series of chiral columns includingAD-3, AS-H, OJ-3, OD-3, AY-3 and IC-3, 4.6×100 mm, 3 um column at a flowrate of 4 mL/min with a gradient solvent Mobile phase A (MPA, CO₂):Mobile phase B (MPB, MeOH+0.05% (v/v) IPAm) (0.01 min, 10% MPB; 3 min,40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB). SFC preparative wasperformed on Thar 80 preparative SFC system with a UV/Vis detector andseries of chiral preparative columns including AD-H, AS-H, OJ-H, OD-H,AY-H and IC-H, 30×250 mm, Sum column at a flow rate of 65 mL/min with agradient solvent Mobile phase A (MPA, CO₂): Mobile phase B (MPB,MeOH+0.1% (v/v) NH₃H₂O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40%MPB; 6.1-10 min, 10% MPB).

Example B-1 Synthesis of2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile Methyl2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate

To a solution of 3-methyl-4-nitro-1H-pyrazole (40 g, 314.71 mmol) in DMF(700 mL) was added NaH (18.88 g, 472.06 mmol, 60% purity) at 0° C. overa period of 30 min under N₂. The reaction was then stirred at 25° C. for2 h followed by the addition of methyl 2-bromo-2-methylpropanoate (85.46g, 472.06 mmol, 61.04 mL) dropwise at 0° C. The reaction mixture waswarmed to 25° C. and stirred at 25° C. for another 16 h. TLC (petroleumether/ethyl acetate=5:1) showed the starting material was consumedcompletely. The reaction was quenched by ice water slowly and thenextracted with EtOAc (3×700 mL). The combined organic phase was washedwith brine (3-200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (petroleum ether/ethyl acetate=30:1-15:1), to yield thedesired product as a light yellow solid (69.70 g, 97.47%). ¹H NMR (400MHz, CDCl₃): δ 8.29 (s, 1H), 3.72 (s, 1H), 2.51 (s, 1H), 1.84 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid

To a mixture of methyl2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g, 306.75mmol) in THF (1 L) and H₂O (250 mL) was added LiOH H₂O (15.45 g, 368.10mmol) at 25° C. under N₂. The mixture was then stirred at 25° C. for 16h. TLC (petroleum ether/ethyl acetate=5:1) showed the reaction wascompleted. The reaction mixture was concentrated in vacuo. The residualaqueous solution was washed with ethyl acetate (50 mL). The aqueousphase was then cooled to 0° C., adjusted to approximately pH 1-2, andfiltered to yield the desired product as a white solid (53 g, 81.04%).¹H NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H), 2.48 (s, 1H), 1.83 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide

To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoicacid (25 g, 117.27 mmol) in DCM (500 mL) was added 8 drops of DMF,followed by oxalyl dichloride (29.77 g, 234.54 mmol) at 0° C. under N₂.Then the mixture was stirred at 25° C. for a further 2 h. TLC (petroleumether/ethyl acetate=3:1) showed reaction was completed. The reactionsolution was concentrated in vacuo. The residue solid was dissolved inTHF (300 mL) and added dropwise into a stirred solution of NH₄OH (413.61g, 11.80 mol, 454.52 mL) at 0° C. The reaction was stirred at 25° C. for1 h. TLC (ethyl acetate) showed reaction was completed. The solution wasthen concentrated in vacuo and partitioned between EtOAc (100 mL) andwater (100 mL), and the aqueous phase was extracted with ethyl acetate(3×80 mL). The combined organic phase was washed with brine (3×40 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo, toyield the desired compound as a yellow solid (22 g, 103.67 mmol, 88.4%).¹H NMR (400 MHz, MeOD): δ 8.81 (s, 1H), 7.16-7.26 (m, 2H), 2.42 (s, 3H),1.71 (s, 3H).

2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile

A solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22g, 103.67 mmol) in POCl₃ (132 g, 860.89 mmol, 80 mL) was stirred at 90°C. for 1 h. TLC showed the reaction was completed. The mixture wascooled to 20° C. and concentrated in vacuo at 50° C. The residue waspoured into ice-water (w/w=1/1) (200 mL) and stirred for 10 min. Theaqueous phase was adjusted to pH=7 with NaHCO₃ solution, extracted withethyl acetate (4-80 mL). The combined organic phase was washed withbrine (40 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo. The desired product was afforded as a yellow solid (20 g,99.35%).

2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile

To a mixture of2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g, 51.5mmol) in EtOH (240 mL) and H₂O (60 mL) was added NH₄Cl (13.77 g, 257.5mmol) in one portion at 25° C., followed by Fe (14.38 g, 257.5 mmol).The mixture was heated to 80° C. and stirred for 1 h. TLC showed thereaction was completed. The solution was cooled to 20° C. The mixturewas extracted with ethyl acetate (3×100 mL), the combined organic layerswere washed with NaHCO₃ solution (50 mL) and brine (50 mL). The organiclayers were dried over Na₂SO₄, filtered and concentrated to afford thedesired product. ¹H NMR (400 MHz, CDCl₃): δ 7.17 (s, 1H), 2.18 (s, 3H),1.91 (s, 6H).

Example B-2 Synthesis of2-[4-[[5-Chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(B-6) 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 5.32mmol) in THF (3 mL) and DCM (12 mL) was added NCS (852 mg, 6.38 mmol) inone portion at 25° C. The mixture was stirred under microwave at 90° C.for 2.5 h. LC/MS showed the reaction was completed. Two new peaks wereshown on LC/MS and 74% of desired (M+H⁺=221.9) was detected. The mixturewas added to brine and extracted with DCM. The organics were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude product waspurified by column chromatography on silica gel (petroleum ether/ethylacetate=50:1-5:1), to yield the desired product as a yellow solid (750mg, 63.37%). ¹H NMR (400 MHz, CDCl₃): δ 10.70 (s., 1H) 8.16 (s, 1H) 4.14(s, 3H).

2,5-Dichloro-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a mixture of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 2.7mmol) and triethylamine (272.92 mg, 2.7 mmol, 373.86 uL) in methanol (2mL) was added MeNH₂ (EtOH solution, 1 mL) in one portion. The solutionwas stirred at 25° C. for 12 h. LC/MS showed the reaction was completed.The mixture was concentrated in vacuo, washed by MTBE and filtered toyield the desired product (493 mg, 84.12%). MS: m/z: 215.1 [M+H]⁺

2-[4-[[5-Chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a solution of2,5-dichloro-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 691.05umol) in t-BuOH (5 mL) was added TFA (78.79 mg, 691.05 umol, 51.16 uL)and 2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (113 mg,691.05 umol). The mixture was stirred at 80° C. for 16 h. LC/MS showedstarting material was consumed and a main peak of desired MS observed.The mixture was concentrated in vacuo. The residue was purified byprep-HPLC (HCl condition), to yield the desired product. ¹H NMR (400MHz, MeOD): δ 8.21 (s, 1H), 6.96 (s, 1H), 3.19 (s, 1H), 2.27 (s, 1H).HPLC: RT 1.91 min. MS: m/z: 345.1 [M+H]⁺.

Example B-3 Synthesis of2-[4-[(5-chloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(B-5) 2,5-dichloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (300 mg,1.35 mmol) in MeOH (5 mL) was added NaOMe (145.85 mg, 2.7 mmol) in oneportion at 25° C. The mixture was stirred at 60° C. for 12 h. LC/MSshowed the reaction was completed. The residue was poured into water (10mL) and stirred for 5 min. The aqueous phase was extracted with ethylacetate (3×10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the crude2,5-dichloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (280 mg crude) whichwas used in the next step without further purification.

2-[4-[(5-chloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of 2,5-dichloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (150mg, 687.95 μmol) and2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (135.56 mg,825.54 μmol) in t-BuOH (5 mL) was added TFA (156.88 mg, 1.38 mmol,101.87 L) in one portion at 25° C. under N₂. The mixture was stirred at100° C. for 12 h. The mixture was concentrated when HPLC indicated thereaction had reached completion. The crude product was purified byprep-HPLC (neutral) to yield the desired product. ¹H NMR (400 MHz,MeOD): δ 8.249 (s, 1H), 6.827 (s, 1H), 4.072 (s, 3H), 2.274 (s, 3H),2.274 (s, 6H). HPLC: RT 2.58 min. MS: m/z: 345.1 [M+H]⁺.

Example B-4 Synthesis of5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine(B-8) and5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine(B-9)Trimethyl-[2-[(2,4,5-trichloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]silane

To a solution of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (800 mg,3.60 mmol) in DMF (8 mL) was added NaH (158 mg, 3.96 mmol, 60% purity)at 0° C. under N₂. The solution was stirred at 0° C. for 30 min. ThenSEM-Cl (719 mg, 4.32 mmol) was added to the solution at 0° C. Thesolution was stirred at 25° C. for 2.5 h. To the mixture was poured intoNH₄Cl solution. The solution was extracted with ethyl acetate (3×15 mL).The organic layers were combined, washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to afford the desired product as abrown oil (1.20 g, 94.5%). The product was used in the next reactionwithout further purification. LC/MS: RT 1.897 min, m/z=352.1, 354.1[M+H]⁺.

2-[(2,5-dichloro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

To a solution oftrimethyl-[2-[(2,4,5-trichloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]silane(850 mg, 2.41 mmol) in methanol (5 mL) was added NaOMe (260 mg, 4.82mmol) in one portion at 25° C. under N₂. The mixture was stirred at 25°C. for 2 h. The mixture was poured into water (10 mL), extracted withethyl acetate (3-3 mL). The combined organic phase was washed with brine(10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethylacetate=5:1) to afford the desired product as a white solid (500 mg,59.57%).

5-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine

To a mixture of2-[(2,5-dichloro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(250 mg, 718 umol) and 1,5-dimethyl-1H-pyrazol-4-amine and1,3-dimethyl-1H-pyrazol-4-amine (88 mg, 790 umol) in 1,4-dioxane (5 mL)was added Pd₂(dba)₃ (66 mg, 71.8 umol), BINAP (45 mg, 71.8 umol) andCs₂CO₃ (702 mg, 2.15 mmol) in one portion at 25° C. under N₂. Themixture was stirred at 90° C. for 12 h. The mixture was concentrated invacuo at 35° C. The residue was poured into water, extracted with EtOAc(3×20 mL). The combined organic phase was washed with brine (2×10 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by prep-TLC (SiO₂, petroleum ether/ethylacetate=3:1) to afford the desired compounds as a white solid (250 mg,82.34%).

5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine&5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine

To a solution of5-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine(250 mg, 591.04 μmol) in DCM (10 mL) was added TFA (2 mL) in one portionat 25° C. The mixture was stirred at 40° C. for 3 hours. The mixture wasconcentrated in vacuo at 35° C. The crude product was dissolved in THF(10 mL) and sat. NaHCO₃ solution (10 mL) was added. The mixture wasstirred at 25° C. for 12 h. The aqueous phase was extracted with ethylacetate (3×20 mL). The combined organic phase was washed with brine(2×10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-HPLC (HCl acidic condition) togive5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amineand5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine.

5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine

¹H NMR (400 MHz, MeOD): δ7.816 (s, 1H), 7.023 (s, 1H), 4.208 (s, 3H),3.929 (s, 3H) 2.337 (s, 3H). HPLC: RT 2.29 min. MS: m/z: 293.1 [M+H]⁺.

5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine

¹H NMR (400 MHz, MeOD): δ8.014 (s, 1H), 7.019 (s, 1H), 4.207 (s, 3H),3.961 (s, 3H) 2.276 (s, 3H). HPLC: RT 2.18 min. MS: m/z: 293.1 [M+H]⁺.

Example B-5 Synthesis of5-chloro-N²-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine(B-1) and5-chloro-N²-(1,3-dimethylpyrazol-4-yl)-N′-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine&5-chloro-N²-(1,3-dimethyl-1H-pyrazol-4-yl)-N′-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine(B-4)2,5-dichloro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine

To a solution oftrimethyl-[2-[(2,4,5-trichloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]silane(1.20 g, 3.40 mmol) in ethanol (20 mL) was added MeNH₂ (640 mg, 6.80mmol, 33% purity in EtOH). The mixture was stirred at 25° C. for 24 h.TLC (petroleum ether:ethyl acetate=5:1) showed the reaction wascompleted. The mixture was concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=100:1-ethyl acetate) to afford the desired product as acolorless gum (600 mg, 50.81%). ¹H NMR (400 MHz, CDCl₃): δ6.93 (s, 1H),5.95 (br, 1H), 5.47 (s, 2H), 3.50-3.54 (t, 2H), 3.17-3.18 (d, 3H),0.90-0.94 (t, 2H), 0.02 (s, 9H). LC/MS: RT 0.954 min, m/z=347.1, 349.1[M+H]⁺.

5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-2,4-diamine

A mixture of2,5-dichloro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine(400 mg, 1.15 mmol), 1,5-dimethylpyrazol-4-amine (89 mg, 805 umol),Cs₂CO₃ (1.12 g, 3.45 mmol), XPhos (55 mg, 115 umol) and Pd₂(dba)₃ (105mg, 115 umol) in 1,4-dioxane (20 mL) was degassed and purged with N₂ for3 times, and then the mixture was stirred at 110° C. for 16 h under N₂.TLC (petroleum ether/ethyl acetate=10:1) showed the reaction wascompleted. The solution was concentrated in vacuo to give a residue. Tothe residue was added water (10 mL), extracted with ethyl acetate (3×15mL). Organic layers were combined, washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give a crude product. The crude waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=30:1-10:1) to afford a mixture that contained the two desiredproducts as a colorless gum (260 mg, ratio-1:1, 53.6%). The mixture wasused in the next step without further purification. LC/MS: RT 1.449 min,m/z=422.3 [M+H]⁺.

5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamineand5-chloro-N2-(1,3-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine&5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

To a solution of a mixture of5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-2,4-diamine(260 mg, 616 μmol, also containing5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine)in DCM (20 mL) was added TFA (6.16 g, 54.03 mmol). The mixture wasstirred at 50° C. for 3 h. TLC (petroleum ether/ethyl acetate=1:1)showed the reaction was completed. The solution was concentrated invacuo. The residue was dissolved in THF (20 mL) and 20 mL of sat. NaHCO₃solution was added to the solution. Then the solution was stirred at 25°C. for 6 h. The solution was extracted with ethyl acetate (3×20 mL),organic layers were combined, washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated to give a crude product. The crudeproduct was purified by prep-HPLC (neutral condition) and lyophilized toafford the desired products.

5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

¹H NMR (400 MHz, CDCl3): δ9.19 (br, 1H), 7.59 (s, 1H), 6.34 (s, 1H),6.03 (br, 1H), 5.69 (br, 1H), 3.73 (s, 3H), 3.10-3.13 (d, 3H), 2.17 (s,3H). HPLC: RT 1.691 min. MS: m/z: 292.1 [M+H]⁺.

5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

¹H NMR (400 MHz, CDCl3): δ9.13 (br, 1H), 7.73 (s, 1H), 6.42 (s, 1H),6.18 (br, 1H), 5.73 (br, 1H), 3.80 (s, 3H), 3.10-3.13 (d, 3H), 2.25 (s,3H). HPLC: RT 1.770 min. MS: m/z: 292.1 [M+H]⁺.

Example B-6 Synthesis of2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(B-2) 2,5-dichloro-N-ethyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(400 mg, 1.13 mmol) in ethanol (10 mL) was added ethanamine (61 mg, 1.36mmol) dropwise at 25° C. The mixture was stirred at 25° C. for 2 h. Themixture was concentrated in vacuo at 35° C. The residue was poured intowater (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). Thecombined organic phase was washed with brine (2×10 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=5:1) to affordthe desired product as a white solid (250 mg, 61.23%). LC/MS: RT 1.015min, m/z=361 [M+H]⁺.

2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of 2, 5-dichloro-N-ethyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine (240 mg, 664.19 umol) and2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (120 mg,730.61 umol) in 1,4-dioxane (5 mL) was added Pd₂(dba)₃ (61 mg, 66.42umol), X-Phos (32 mg, 66.42 umol) and Cs₂CO₃ (650 mg, 1.99 mmol) in oneportion at 25° C. under N₂. The mixture was stirred at 90° C. for 12 h.The mixture was cooled to 25° C. and concentrated in vacuo at 35° C. Theresidue was poured into water (10 mL). The aqueous phase was extractedwith ethyl acetate (3×20 mL). The combined organic phase was washed withbrine (2×10 mL), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by TLC (petroleum ether/ethylacetate=3:1) to afford the desired product as a white solid (250 mg,quantitative). LC/MS: RT 0.883 min, m/z=489 [M+H]⁺.

2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(150 mg, 306.69 μmol) in DCM (10 mL) was added TFA (2 mL) in one portionat 25° C. The mixture was stirred at 25° C. for 3 h. The reactionmixture was concentrated in vacuo to remove DCM. The crude product wasdissolved in THF (10 mL) and aq. NaHCO₃ (10 mL) was added. The mixturewas stirred at 25° C. for 12 h. The mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by prep-HPLC (neutral condition) to afford thedesired product. ¹H NMR (400 MHz, CDCl3): δ 8.518 (s, 1H), 8.232 (s,1H), 6.602 (s, 1H), 6.224 (s, 1H) 5.747 (s, 1H) 3.673-3.606 (m, 2H)2.288 (s, 3H) 1.968 (s, 6H) 1.363-1.327 (t, 3H, J=7.2 Hz). HPLC: RT2.609 min. MS: [M+H]⁺ m/z: 359.1

Example B-7 Synthesis of2-[4-[[5-chloro-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(B-3)2-[(2,5-dichloro-4-ethoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

To a mixture of2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(500 mg, 1.42 mmol) in ethanol (5 mL) was added freshly prepared NaOEt(193.26 mg, 2.84 mmol) in one portion at 25° C. The mixture was stirredat 25° C. for 3 h. The reaction mixture was quenched by water, extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by prep-TLC (SiO₂, petroleum ether/ethylacetate=8:1) to afford the desired product (280 mg, 54.42%). LC/MS: RT1.016 min, m/z=362 [M+H]⁺.

2-[4-[[5-chloro-4-ethoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of2-[(2,5-dichloro-4-ethoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(280 mg, 773 umol) and2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (140 mg, 850umol) in dioxane (5 mL) was added Pd₂(dba)₃ (71 mg, 77.3 umol), Cs₂CO₃(755 mg, 2.32 mmol) and BINAP (48 mg, 77 umol) in one portion at 25° C.under N₂. The mixture was heated to 120° C. and stirred for 16 h. Themixture was cooled to 25° C. and concentrated in vacuo at 35° C. Theresidue was poured into water, extracted with ethyl acetate. Thecombined organic phase was washed with brine, dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=5:1) to afford the desired product as a whitesolid (315 mg, 83.18%). LC/MS: RT 0.993 min, m/z=490 [M+H]⁺.

2-[4-[[5-chloro-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of2-[4-[[5-chloro-4-ethoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(315 mg, 643 mmol) in DCM (10 mL) was added TFA (2 mL) in one portion at25° C. The mixture was stirred at 25° C. for 3 h. The reaction mixturewas concentrated in vacuo to remove DCM. The residue was dissolved inTHF (10 mL) and added with aq. NaHCO₃ (10 mL). The mixture was stirredat 25° C. for 12 h, and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo, purified by prep-HPLC (neutral condition) toafford the desired product. ¹H NMR (400 MHz, CDCl3): δ 8.720 (s, 1H),8.222 (s, 1H), 6.703-6.698 (d, 1H, J=2 Hz), 6.327 (s, 1H), 4.608-4.555(m, 2H), 2.314 (s, 3H), 1.990 (s, 6H), 1.535-1.500 (t, 3H, J=7 Hz).HPLC: RT 2.847 min. MS: m/z: 360.1 [M+H]⁺.

Example B-8 Synthesis of2-(4-((6-methoxy-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(B-7) 2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

To a solution of 2,6-dichloro-9H-purine (3 g, 15.87 mmol) in DMF (10 mL)was added NaH (698 mg, 17.46 mmol) at 0° C. The mixture was stirred at0° C. for 1 h. Then SEM-Cl (3.18 g, 19.05 mmol) was added to thesuspension, the mixture was stirred at 25° C. for 2 h. The reactionmixture was quenched by addition of H₂O (10 mL) at 25° C. and extractedwith ethyl acetate (3-330 mL). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated invacuo to get a residue. The residue was purified by columnchromatography on silica gel (petroleum ether/ethyl acetate=5:1-3:1) toafford the desired product was a white solid (3.8 g, 75%). LC/MS: RT0.89 min, m/z=319 [M+H]⁺.

2-chloro-6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

To a solution of2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (1.3 g, 4.07mmol) in MeOH (20 mL) was added sodium methoxide (330 mg, 6.11 mmol).The mixture was stirred at 25° C. for 10 h. The reaction mixture wasconcentrated in vacuo to remove MeOH. The residue was diluted with H₂O(30 mL) and extracted with DCM (3×30 mL). The combined organic layerswere washed with brine (25 mL×2), dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byprep-TLC (SiO₂, petroleum ether/ethyl acetate=3:1) to afford the desiredcompound as a white solid (600 mg, 47%). LC/MS: RT 0.88 min, m/z=315[M+H]⁺.

2-(4-((6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

To a solution of2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (203 mg,1.24 mmol),2-chloro-6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (300mg, 952.86 umol) in 1,4-dioxane (25 mL) was added Pd₂(dba)₃ (87 mg,95.29 umol), Cs₂CO₃ (621 mg, 1.91 mmol) and X-Phos (91 mg, 190.57 umol)under N₂. The mixture was stirred at 110° C. for 10 h. The reactionmixture was concentrated in vacuo to remove 1,4-dioxane. The residue wasdiluted with H₂O (20 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with brine (2×15 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by prep-TLC (SiO2, petroleum ether/ethylacetate=1:1) to afford the desired product as a white solid (320 mg,76%). LC/MS: RT 0.82 min, m/z=443 [M+H]⁺.

2-(4-((6-methoxy-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

To a solution of2-(4-((6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(162 mg, 366.03 umol) in DCM (10 mL) was added TFA (3.34 g, 29.28 mmol)in one portion at 25° C. The mixture was heated to 40° C. and stirredfor 6 h. The reaction mixture was concentrated in vacuo to get aresidue. The residue was dissolved in THF (10 mL) and added with aq.NaHCO₃ (10 mL). The mixture was stirred at 25° C. for 12 h. The mixturewas extracted with ethyl acetate (30 mL). The organic layer was washedwith brine (15 mL), dried over Na₂SO₄, filtered and concentrated invacuo to get a residue. The residue was purified by prep-TLC (SiO₂,DCM:MeOH=10:1) to afford the desired product. ¹H NMR (400 MHz, DMSO-d6):δ 12.64 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 4.04 (s, 3H),2.19 (s, 3H), 1.94 (s, 6H). HPLC: RT 1.59 min. MS: [M+H]⁺ m/z: 313.2.

Example B-9 Synthesis of2-(4-((5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (7 g, 37.23 mmol)and selectfluor (13.19 g, 37.23 mmol) in CH₃CN (360 mL) and AcOH (72 mL)was degassed and then the mixture was stirred at 60° C. for 16 h underN₂. The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with water (200 mL), adjusted to pH=7 with aq.NaHCO₃, and extracted with EtOAc (3×300 mL). The combined organic layerswere washed with brine (300 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by silica gel column chromatography (PE:EtOAc=10:1 to 5:1) togive 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 22.82%)as a yellow oil. LCMS: RT 0.732 min, m/z=206.0 [M+H]⁺.

2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (2.5g, 12.14 mmol) in DMF (25 mL) was added NaH (582 mg, 14.57 mmol) at 0°C. The mixture was stirred at this temperature for 1 h, and then SEM-Cl(2.43 g, 14.57 mmol) was added dropwise at 0° C. The resulting mixturewas stirred at 25° C. for 1 h. The reaction was slowly poured intoice-water, and then extracted with EtOAc (3×80 mL). The combined organicphase was washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(2.5 g, 61.24%) as a yellow oil. LCMS: RT 0.975 min, m/z=336.1 [M+H]⁺.

2-chloro-5-fluoro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine

To a mixture of2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(1.1 g, 3.27 mmol) in EtOH (15 mL) was added MeNH₂ (522 mg, 5.55 mmol,33% purity) at 0° C. under N₂ and stirred at 25° C. for 8 h. The mixturewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (SiO₂, PE:EtOAc=50:1) to give2-chloro-5-fluoro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine(645 mg, 59.61%) as a yellow syrup. LCMS: RT 0.912 min, m/z=331.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.29 (s, 1H), 6.75 (d, J=2.51 Hz,1H), 5.48 (s, 2H), 3.49-3.56 (m, 2H), 3.19 (d, J=5.02 Hz, 2H), 0.90-0.97(m, 2H).

2-[4-[[5-fluoro-4-(methylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a solution of2-chloro-5-fluoro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine(350 mg, 1.06 mmol) in 1,4-dioxane (5 mL) was added Pd₂(dba)₃ (97 mg,106 umol), Cs₂CO₃ (1.04 g, 3.18 mmol) anddicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (505 mg, 1.06mmol) under N₂. The mixture was stirred at 120° C. for 16 h. The mixturewas concentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=2:1), to give2-[4-[[5-fluoro-4-(methylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(310 mg, 63.77%) as a brown syrup. LCMS: RT 0.807 min, m/z=459.3 [M+H]⁺.

2-(4-((5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

To a solution of2-[4-[[5-fluoro-4-(methylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(120 mg, 261.66 umol) in DCM (5 mL) was added dropwise SnCl₄ (886 mg,3.40 mmol) at 0° C. over 30 min. After addition, the mixture was stirredat this temperature for 30 min. The resulting mixture was stirred at 20°C. for 2 h. The reaction mixture was quenched by addition of H₂O (20 mL)at 0° C., and then added with sat. NaHCO₃ (20 mL) to pH=8 and extractedwith DCM (3×20 mL). The combined organic layers were washed with brine(10 mL), and concentrated under reduced pressure at 20° C. The residuewas dissolved with THF/H₂O (4/1, 20 mL) and added with excessive K₂CO₃.The resulting mixture was stirred at 20° C. for 2 h. The reactionmixture was diluted with H₂O (40 mL) at 0° C., and extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure at20° C. The residue was purified by prep-HPLC (neutral) to give2-(4-((5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile.¹H NMR: (400 MHz. CDCl3): δ ppm 8.87 (br, 1H), 8.21 (s, 1H), 6.31-6.37(m, 1H), 6.25-6.30 (m, 1H), 5.13-5.25 (m, 1H), 3.15 (d, J=4.8 Hz, 3H),2.28 (s, 3H), 1.92 (s, 6H). HPLC: RT 1.992 min. MS: [M+H]⁺ m/z: 329.2.

Example B-10 Synthesis of2-[4-[(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(B-11)2-[(2-chloro-5-fluoro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

To a mixture of2-[(2,4-dichloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(1.16 g, 3.45 mmol) in MeOH (13 mL) was added NaOMe (559 mg, 10.35 mmol)at 0° C. under N₂ and stirred at 25° C. for 2 h. The mixture wasconcentrated under reduced pressure and poured into ice water (12 mL).The aqueous phase was extracted with EtOAc (3×4 mL). The combinedorganic phase was washed with brine (4 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EtOAc=50:1) to afford2-[(2-chloro-5-fluoro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(1.08 g, 94.20%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 6.88-6.91(m, 1H), 5.52 (s, 2H), 4.17 (s, 3H), 3.48-3.54 (m, 2H), 0.89-0.95 (m,2H).

2-[4-[[5-fluoro-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a solution of2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (327 mg, 1.99mmol) in 1,4-dioxane (7 mL) was added Pd₂(dba)₃ (166 mg, 181 umol),Cs₂CO₃ (1.77 g, 5.43 mmol) and XPhos (86 mg, 181 umol) under N₂. Themixture was stirred at 120° C. for 16 h. The mixture was concentratedunder reduced pressure. The residue was purified by prep-TLC (SiO₂,PE:EtOAc=2:1), to give2-[4-[[5-fluoro-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(294 mg, 35.34%) as a yellow solid. LCMS: RT 0.947 min, m/z=460.3[M+H]⁺.

2-[4-[(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a solution of2-[4-[[5-fluoro-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(250 mg, 543.96 umol) in DCM (10 mL) was added SnCl₄ (1.84 g, 7.07 mmol,826.13 uL) at 0° C. under N₂. The mixture was stirred at 25° C. for 2 h.The mixture was poured into ice-water (10 mL) and adjusted to pH=8 byadding aq. NaHCO₃. The reaction mixture was extracted with EtOAc (3×4mL). The combined organic phase was washed with brine (10 mL), andconcentrated under reduced pressure. The residue was dissolved in THF(7.5 mL) and H₂O (2.5 mL), then added with K₂CO₃ (3.38 g, 24.48 mmol).The mixture stirred at 25° C. for 3 h. The reaction mixture wasextracted with EtOAc (3×4 mL). The combined organic phase was washedwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral), to give2-[4-[(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile.¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 2H), 6.49 (t, J=2.51 Hz, 1H), 6.34(s, 1H), 4.11 (s, 3H), 2.30 (s, 3H), 1.98 (s, 6H). HPLC: RT: 2.68 min.MS: [M+H]⁺ m/z=330.2.

Example B-11 Synthesis of2-[4-[(6-ethoxy-9H-purin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(B-12) 2-[(2-chloro-6-ethoxy-purin-9-yl)methoxy]ethyl-trimethyl-silane

To a mixture of2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (3.00 g, 9.40mmol) in EtOH (30 mL) was added fresh EtONa (216 mg, 3.18 mmol, 273 uL)at 25° C. The mixture was stirred at 25° C. for 3 h. The reactionmixture was quenched by adding water (10 mL) at 25° C. and concentrated.Then the mixture was extracted with EtOAc (3×5 mL). The combined organicphase was washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give2-[(2-chloro-6-ethoxy-purin-9-yl)methoxy]ethyl-trimethyl-silane (2.82 g,91.22%) as a white solid. LCMS: RT 0.922 min, m/z=329.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): δ ppm 8.03 (s, 1H), 5.58 (s, 2H), 4.68 (q, J=7.06 Hz,2H), 3.58-3.64 (m, 2H), 1.52 (t, J=7.06 Hz, 3H), 0.91-0.96 (m, 2H) −0.03(s, 9H).

2-[4-[[6-ethoxy-9-(2-trimethylsilylethoxymethyl)purin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of2-[(2-chloro-6-ethoxy-purin-9-yl)methoxy]ethyl-trimethyl-silane (200 mg,608.14 umol) and2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (119.84 mg,729.77 umol) in 1,4-dioxane (2 mL) was added Cs₂CO₃ (475 mg, 1.46 mmol),XPhos (57 mg, 121.63 umol) and Pd₂(dba)₃ (56 mg, 60.81 umol) at 20° C.under N₂. The mixture was heated to 110° C. and stirred for 5 h. Themixture was cooled to 20° C. and added with water (10 mL), thenextracted with EtOAc (3×5 mL), washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (PE:EtOAc=1:1) to give2-[4-[[6-ethoxy-9-(2-trimethylsilylethoxymethyl)purin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(259 mg, 93.27%) as a yellow oil. LCMS: RT 0.874 min, m/z=457.3 [M+H]+

2-[4-[(6-ethoxy-9H-purin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of2-[4-[[6-ethoxy-9-(2-trimethylsilylethoxymethyl)purin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(256 mg, 560.64 umol) in DCM (20 mL) was added TFA (6.16 g, 54.03 mmol,4 mL) at 20° C. under N₂. The mixture was heated to 40° C. and stirredfor 5 h. The mixture was cooled to 20° C. and concentrated. The residuewas adjusted pH=7-8 by adding aq.NaHCO₃. The mixture was extracted withEtOAc (10 mL×3), washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (neutral) to give2-[4-[(6-ethoxy-9H-purin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile.LCMS: RT 0.629 min, m/z=327.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD): δ ppm 8.25(s, 1H), 7.90 (s, 1H), 4.59 (q, J=7.06 Hz, 2H), 2.25-2.29 (m, 3H), 1.99(s, 6H), 1.48 (t, J=7.06 Hz, 3H). HPLC: RT: 1.652 min. MS: [M+H]⁺ m/z:327.2.

Example B-12 Synthesis of2-[4-[(5-cyclopropyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(B-13)2-[(2,4-dichloro-5-cyclopropyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

A mixture of2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(3 g, 6.75 mmol), cyclopropylboronic acid (928 mg, 10.80 mmol),Pd(dppf)Cl₂ (494 mg, 675 umol), Ag₂O (782 mg, 3.38 mmol) and K₃PO₄ (4.3g, 20.25 mmol) in 1,4-dioxane (30 mL) was degassed and purged with N₂for 3 times. The mixture was stirred at 90° C. for 16 h under N₂. Themixture was cooled to 20° C. and poured into ice-water (30 mL). Theaqueous phase was extracted with EtOAc (3-20 mL). The combined organicphase was washed with brine (3×20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EtOAc=5:1), to give2-[(2,4-dichloro-5-cyclopropyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(2 g, 82.69%) as a yellow solid. LCMS: RT 1.069 min, m/z=358.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ 6.97 (d, J=1.13 Hz, 1H), 5.51-5.53 (m, 2H),3.49-3.53 (m, 2H), 2.11-2.20 (m, 1H), 0.96-1.00 (m, 2H), 0.90-0.94 (m,2H), 0.64 (dd, J=5.21, 1.57 Hz, 2H), −0.04 (s, 9H).

2-[(2-chloro-5-cyclopropyl-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

To a mixture of2-[(2,4-dichloro-5-cyclopropyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(1 g, 2.79 mmol) in MeOH (2 mL) was added CH₃ONa (880 mg, 16.29 mmol) inone portion at 0° C., warmed to 20° C. and stirred for 16 h. The mixturewas poured into ice-water (10 mL). The aqueous phase was extracted withEtOAc (3×10 mL). The combined organic phase was washed with brine (10mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure, to give2-[(2-chloro-5-cyclopropyl-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(1 g, crude) as a yellow oil. LCMS: RT 1.051 min, m/z=354.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₁): δ 6.71 (s, 1H), 5.47 (s, 2H), 4.14 (s, 3H),3.44-3.53 (m, 2H), 2.06-2.15 (m, 1H), 0.89-0.95 (m, 4H), 0.58-0.64 (m,2H), −0.05 (s, 9H).

2-[4-[[5-cyclopropyl-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

A mixture of2-[(2-chloro-5-cyclopropyl-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(300 mg, 847.65 umol),2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (278 mg, 1.70mmol), Pd₂(dba)₃ (78 mg, 84.77 umol), XPhos (81 mg, 169.53 umol) andCs₂CO₃ (690 mg, 2.12 mmol) in 1,4-dioxane (5 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 110° C. for 16h under N₂. The mixture was cooled to 20° C. and poured into ice-water(5 mL). The aqueous phase was extracted with EtOAc (3×4 mL). Thecombined organic phase was washed with brine (4 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, PE:EtOAc=3:1), to give2-[4-[[5-cyclopropyl-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(279 mg, 68.34%) as a yellow oil. LCMS: RT 1.021 min, m/z=482.4 [M+H]⁺.

2-[4-[(5-cyclopropyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of2-[4-[[5-cyclopropyl-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(279 mg, 579.25 umol) in DCM (20 mL) was added TFA (6.16 g, 54.03 mmol,4 mL) at 0° C. under N₂. The mixture was stirred at 20° C. for 8 h andconcentrated under reduced pressure. The residue in THF (20 mL) and H₂O(5 mL) was added with K₂CO₃ (7 g, 50.65 mmol). The mixture was stirredat 20° C. for 12 h. The mixture was poured into ice-water (10 mL). Theaqueous phase was extracted with EtOAc (3×10 mL). The combined organicphase was washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (neutral), to give2-[4-[(5-cyclopropyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile.¹H NMR (400 MHz, CDCl₃): δ 8.71 (br. s., 1H), 8.24 (s, 1H), 6.33 (s,2H), 4.10 (s, 3H), 2.29 (s, 3H), 2.03-2.12 (m, 1H), 1.93 (s, 6H),0.84-0.90 (m, 2H), 0.58 (dd, J=5.21, 1.69 Hz, 2H). HPLC: RT: 2.77 min.MS: [M+H]J m/z=352.2.

Example B-13 Synthesis of2-(4-((4-methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(B-14)2-chloro-4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of CuI (146 mg, 0.77 mmol), KF (668 mg, 11.5 mmol) and1,10-phenanthroline (138 mg, 0.77 mmol) in DMSO (2 mL) was added (MeO)₃B(1.2 g, 11.5 mmol),2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(1.7 g, 3.83 mmol) and TMSCF₃ (1.63 g, 11.5 mmol). The reaction mixturewas stirred at 60° C. for 12 h under N₂. The mixture was cooled to 20°C. and poured into ice-water (20 mL). The aqueous phase was extractedwith EtOAc (2-20 mL). The combined organic phase was washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue, which was purified by silica gelcolumn chromatography (PE:EtOAc=20:1 to 1:1) to give2-chloro-4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(900 mg, 61.54%) as a yellow solid. LCMS: RT 1.222 min, m/z=382.1[M+H]⁺.

2-(4-((4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

To a solution of2-chloro-4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(200 mg, 0.52 mmol) in 1, 4-dioxane (5 mL) was added2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (94 mg, 0.57mmol), XPhos (248 mg, 0.52 umol), Cs₂CO (170 mg, 0.52 mmol) andPd₂(dba), (477 mg, 0.52 umol) under N₂, then the mixture was stirred at100° C. for 2 h. The reaction mixture was cooled to ambient temperatureand poured into ice-water (5 mL), and extracted with EtOAc (3×5 mL).Combined organic layers were washed with brine (10 mL), dried overNa₂SO₄ and concentrated under reduced pressure to give a residue, whichwas purified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give2-(4-((4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(200 mg, 75.33%) as a yellow solid. LCMS: RT 1.412 min, m/z=510.4[M+H]⁺.

2-(4-((4-methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

To a solution of2-(4-((4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(150 mg, 0.29 mmol) in DCM (4 mL) was added TFA (671 mg, 0.44 mL, 5.89mmol) at 0° C., then the mixture was stirred at 40° C. for 24 h. Thereaction mixture was concentrated under reduced pressure. The residue inTHF (4 mL) and water (4 mL) was added with K₂CO₃ (540 mg, 3.91 mmol) at20° C. Then the mixture was stirred at 50° C. for 4 h. The mixture wasconcentrated under reduced pressure to give a residue, which waspurified by prep-HPLC (FA) to give2-(4-((4-methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile.¹H NMR (400 MHz, CHLOROFORM-d): δ 8.74 (br. s., 1H), 8.22 (s, 1H), 7.14(br. s., 1H), 6.37 (s, 1H), 4.10 (s, 3H), 2.30 (s, 3H), 1.98 (s, 6H).HPLC: RT: 2.98 min. MS: [M+H]⁺ m/z: 380.1.

Other compounds of structure (B-I) were prepared according to the aboveprocedures.

C: Compound Preparation

In the following Examples, all non-aqueous reactions were carried out inoven-dried or flame-dried glassware under nitrogen atmosphere. Allchemicals were purchased from commercial vendors and used as is, unlessotherwise specified. Reactions were magnetically stirred and monitoredby thin layer chromatography (TLC) with 250 μm pre-coated silica gelplates, visualized either with UV, or in an iodine chamber. Flash columnchromatography was performed using silica gel (100-200 mesh). Chemicalshifts are reported relative to chloroform (87.26), methanol (63.31), orDMSO (82.50) for 1H NMR. HPLC analysis was performed on Shimadzu 20ABHPLC system with a photodiode array detector and Luna-C18(2) 2.0×50 mm,5 μm column at a flow rate of 1.2 mL/min with a gradient solvent Mobilephase A (MPA, H2O+0.037% (v/v) TFA): Mobile phase B (MPB, ACN+0.018%(v/v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected under 220 and 254 nmor used evaporative light scattering (ELSD) detection as well aspositive electrospray ionization (MS). Semi-preparative HPLC wasperformed by either acidic or neutral condition. Acidic: Luna C18 100×30mm, 5 μm: MPA: HCl/H₂O=0.04%, or formic acid/H₂O=0.2% (v/v); MPB: ACN.Neutral: Waters Xbridge 150×25, 5 μm; MPA: 10 mM NH₄HCO₃ in H₂O; MPB:ACN. Gradient for both conditions: 10% of MPB to 80% of MPB within 12min at a flow rate of 20 mL/min, then 100% MPB over 2 min, 10% MPB over2 min, UV detector. Compounds were named by using either ChemBioDrawUltra 13.0 or Chemaxon.

Example C-1 and C-2 Synthesis of6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-9H-purin-2-amine(C-1) and6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine(C-2) 2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane

To a solution of compound 2,6-dichloro-9H-purine (10.00 g, 52.91 mmol)in DMF (100 mL) was added NaH (2.54 g, 63.49 mmol, 60% purity) at 0° C.over a period of 15 min under N₂. The mixture was then warmed up to 20°C. and stirred at 20° C. for 30 min. Then compound SEMCl (11.35 g, 63.49mmol) was dropwise at 0° C. over a period of 15 min under N₂. Themixture was then warmed up to 20° C. and stirred at 20° C. for 3 h. Thereaction was quenched by pouring into ice-water (500 mL) and extractedwith MTBE (3×200 mL), washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (PE:EtOAc=20:1 to 2:1)to give compound2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane as a lightyellow solid.

2-[(2-chloro-6-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane

To a mixture of compound2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (5.00 g, 15.66mmol) and cyclopropaneboronic acid (4.04 g, 46.98 mmol) in 1,4-dioxane(50 mL) was added Ag2O (1.81 g, 7.83 mmol), K3PO4 (9.97 g, 46.98 mmol)and Pd(dppf)Cl2 (1.15 g, 1.57 mmol) in one portion at 20° C. under N2.The mixture was then heated to 90° C. and stirred for 5 h. The mixturewas cooled to 20° C., filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(PE:EtOAc=10:1 to 1:1) to give compound2-[(2-chloro-6-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane asa light yellow solid.

6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-yl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amineand6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine

To a mixture of compound2-[(2-chloro-6-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane(500 mg, 1.54 mmol) and1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-amine and1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-amine (405 mg, 2.31mmol, mixture) in 1,4-dioxane (15 mL) was added XPhos (147 mg, 308umol), Cs2CO3 (1.20 g, 3.70 mmol) and Pd2(dba)3 (141 mg, 154 umol) inone portion at 20° C. under N2. The mixture was then heated to 110° C.and stirred for 16 h. The mixture was cooled to 20° C., added with EtOAc(5 mL), filtered and the filtrate was concentrated under reducedpressure. The residue was purified by prep-TLC (PE:EtOAc=1:1) to givecrude product compound6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-yl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amineand6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amineas a red brown oil which was used into the next step without furtherpurification.

6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-9H-purin-2-amineand6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine

To a mixture of compound6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-yl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amineand6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine(220 mg, 474 umol) in DCM (20 mL) was added TFA (6.16 g, 54.03 mmol) at0° C. The mixture was heated to 40° C. and stirred for 3.5 h. Themixture was cooled to 25° C. and adjusted pH to 7 by adding aq. NaHCO3and stirred for 10 min. The mixture was then extracted with EtOAc (3×5mL). The combined organic phase was washed with brine (5 mL), dried overanhydrous Na2SO₄, filtered and concentrated under reduce pressure. Theresidue was purified by prep-HPLC (FA condition) to give6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-9H-purin-2-amineand6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine.

6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-9H-purin-2-amine

¹H NMR (400 MHz, CDCl3): δ ppm 7.95 (s, 1H), 7.68 (s, 1H), 6.50 (br. s.,1H), 4.38-5.08 (m, 5H), 2.66 (d, J=4.52 Hz, 1H), 2.26 (s, 3H), 1.33-1.47(m, 2H), 1.14-1.24 (m, 2H). HPLC: RT 1.574 min. MS: m/z: 334.2 [M+H]+.

6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine

¹H NMR (400 MHz, CDCl3): δ ppm 11.66 (br. s., 1H), 7.67 (s, 1H) 7.21 (s,1H), 6.23 (s, 1H), 4.57-4.83 (m, 5H), 2.59 (br. s., 1H), 2.11-2.24 (m,3H), 1.29 (br. s., 2H), 1.03-1.14 (m, 2H). HPLC: RT 1.556 min. MS: m/z:334.2 [M+H]+.

Example C-3 Synthesis of6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine(C-3)6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amine

To a solution of2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (180 mg,554.05 μmol) in 1,4-dioxane (10 mL) was added compound1-(difluoromethyl)-3-methyl-1H-pyrazol-4-amine (98 mg, 664.86 umol),XPhos (53 mg, 110.81 umol), Cs₂CO₃ (361 mg, 1.11 mmol) and Pd₂(dba)₃ (51mg, 55.41 umol). The mixture was stirred at 110° C. for 6 h under N₂.The mixture was concentrated under reduced pressure to give a residue,which was purified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give compound6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amineas a yellow solid. LCMS: RT 0.880 min, m/z=436.1 [M+H]⁺.

6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine

To a solution of6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine(205 mg, 476.67 umol) in DCM (20 mL) was added TFA (6.8 g, 59.65 mmol)in one portion at 25° C. The mixture was stirred at 40° C. for 4 h. Thereaction mixture was concentrated under reduced pressure to get aresidue, which was dissolved in THF (20 mL) and treated with aq. NaHCO₃(20 mL). The mixture was stirred at 25° C. for 12 h. The mixture wasextracted with EtOAc (30 mL). The organic layer was separated and washedwith brine (15 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to get a residue, which was purified by prep-HPLC(neutral) to get6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine.¹H NMR (400 MHz, MeOD): δ 8.40 (s, 1H), 8.07 (s, 1H), 7.12-7.48 (m, 1H),2.56-2.66 (m, 1H), 2.29 (s, 3H), 1.27-1.35 (m, 2H), 1.12-1.21 (m, 2H).HPLC: RT 1.96 min. MS: m/z: 306.2 [M+H]⁺.

Example C-4 Synthesis of6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine(C-4)6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amine

To a solution of2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (180 mg,554.05 umol) in 1,4-dioxane (10 mL) was added1-(difluoromethyl)-5-methyl-1H-pyrazol-4-amine (98 mg, 664.86 umol),XPhos (53 mg, 110.81 umol), Cs₂CO₃ (361 mg, 1.11 mmol) and Pd₂(dba)₃ (51mg, 55.41 umol). The mixture was stirred at 110° C. for 6 h under N₂.The mixture was concentrated under reduced pressure to give a residue,which was purified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amineas a yellow solid. LCMS: RT 2.831 min, m/z=436.1 [M+H]⁺.

6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine

To a solution of6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amine(140 mg, 321.43 umol) in DCM (20 mL) was added TFA (6.8 g, 59.65 mmol)in one portion at 25° C. The mixture was heated to 40° C. and stirredfor 4 h. The reaction mixture was concentrated under reduced pressure toget a residue, which was dissolved in THF (20 mL) and added withaq.NaHCO₃ (20 mL). The mixture was stirred at 25° C. for 12 h. Themixture was extracted with EtOAc (30 mL). The organic layer wasseparated and washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to get a residue, which was purifiedby prep-HPLC (neutral) to get6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine.¹H NMR (400 MHz, MeOD): δ 8.02 (br. s., 1H), 7.93 (s, 1H), 7.24-7.57 (m,1H), 2.59 (br. s., 1H), 2.39 (s, 3H), 1.23-1.32 (m, 2H), 1.08-1.18 (m,2H). HPLC: RT: 1.87 min. MS: m/z: 306.1 [M+H]⁺.

Example C-5 and C-6 Synthesis of6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine (C-5) and6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine (C-6)6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9-(2-trimethylsilylethoxymethyl)purin-2-amine

2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (400 mg, 1.23mmol), 1,3-dimethyl-1H-pyrazol-4-amine and1,5-dimethyl-1H-pyrazol-4-amine (205 mg, 1.85 mmol, mixture), XPhos (117mg, 246.24 umol), Cs₂CO₃ (963 mg, 2.95 mmol) and Pd₂(dba)₃ (112 mg,123.12 umol) in 1,4-dioxane (10 mL) were taken up into a microwave tube.The sealed tube was heated at 110° C. for 14 h under microwaveirradiation. After cooled to 25° C., EtOAc (10 mL) was added. Themixture was then filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=10:1to 0:1) to give6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amineand6-cyclopropyl-N-(1,5-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amineas a yellow oil.

6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine and6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine

To a solution of6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amineand6-cyclopropyl-N-(1,5-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine(200 mg, 500.54 μmol, mixture) in DCM (20 mL) was added TFA (6.16 g,54.02 mmol) in one portion at 0° C. Then the mixture was heated to 40°C. and stirred for 6 h. The mixture was adjusted pH to 7-8 by adding aq.sat. NaHCO₃ and stirred for 10 min. The aqueous phase was extracted withEtOAc (3×5 mL). The combined organic phase was washed with brine (5 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (FA condition) andfurther separated by SFC to give6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine and6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine. LCMS: RT0.148 min, m/z=270.2 [M+H]⁺.

6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine

¹H NMR (400 MHz, CDCl₃): δ ppm 11.89 (br. s., 1H), 7.58 (s, 1H), 7.17(s, 1H), 6.32 (br. s., 1H), 3.83 (s, 1H), 3.75 (s, 3H), 2.60-2.70 (m,1H), 2.23 (s, 1H), 2.17 (s, 3H), 1.37 (br. s., 2H), 1.17 (d, J=4.52 Hz,2H), 0.08 (s, 1H). HPLC: RT: 1.287 min. MS: m/z: 270.2 [M+H]⁺.

6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine

¹H NMR (400 MHz, CDCl3): δ ppm 10.46 (br. s., 1H), 7.69 (s, 1H), 7.53(s, 1H), 6.34 (s, 1H), 3.84 (s, 3H), 2.63-2.72 (m, 1H), 2.25 (s, 3H),1.34-1.41 (m, 2H), 1.18 (dd, J=8.16, 3.31 Hz, 2H). HPLC: RT: 1.262 min.MS: m/z: 270.1 [M+H]⁺.

Example C-7 Synthesis of6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine(C-7)6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amine

To a solution of2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (232 mg,714.14 umol) in 1,4-dioxane (10 mL) was added1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-amine (90 mg, 595.20 umol),XPhos (57 mg, 119.04 umol), Cs₂CO₃ (388 mg, 1.19 mmol) and Pd₂(dba)₃ (55mg, 59.52 umol). The mixture was stirred at 110° C. for 6 h under N₂.The mixture was concentrated under reduced pressure to give a residue,which was purified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amineas a yellow solid. LCMS: RT 0.839 min, m/z=440.3 [M+H]⁺.

6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine

To a solution of6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-amine(160 mg, 363.94 umol) in DCM (20 mL) was added TFA (7.7 g, 67.53 mmol)in one portion at 25° C. The mixture was heated to 40° C. and stirredfor 4 h. The reaction mixture was concentrated under reduced pressure toget a residue, which was dissolved in THF (20 mL) and added with aq.NaHCO₃ (20 mL). The mixture was stirred at 25° C. for 12 h. The mixturewas extracted with EtOAc (30 mL). The organic layer was separated andwashed with brine (15 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to get a residue, which was purified by prep-HPLC(neutral) to get6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-amine.¹H NMR (400 MHz, CDCl₃): δ 11.82-12.27 (m, 1H), 7.62 (s, 1H), 7.19 (s,1H), 6.30 (s, 1H), 3.88 (d, J=6.90 Hz, 2H), 2.63 (d, J=4.14 Hz, 1H),2.21 (s, 3H), 1.36 (br. s., 2H), 1.15 (dd, J=7.65, 2.89 Hz, 3H), 0.53(d, J=7.53 Hz, 2H), 0.33 (d, J=5.02 Hz, 2H). HPLC: RT 1.74 min. MS: m/z:310.2 [M+H]⁺.

Example C-8 Synthesis ofN-(6-cyclopropyl-9H-purin-2-yl)spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine(C-8) [1-[(4-nitropyrazol-1-yl)methyl]cyclopropyl]methanol

To a solution of 3-nitropyrazole (16.61 g, 146 mmol), [1-(hydroxymethyl)cyclopropyl] methanol (15 g, 146 mmol) and PPh₃ (38.52 g, 146 mmol) inTHF (300 mL) was added DIAD (29.7 g, 146 mmol) dropwise at 0° C. over aperiod of 30 min under N₂. The reaction mixture was stirred at 25° C.for another 12 h. The reaction was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(PE:EtOAc=50:1 to 2:1) to give[1-[(4-nitropyrazol-1-yl)methyl]cyclopropyl]methanol as a white solid.

1-[[1-(bromomethyl)cyclopropyl]methyl]-4-nitro-pyrazole

To a mixture of [1-[(4-nitropyrazol-1-yl)methyl]cyclopropyl]methanol (7g, 35.5 mmol) in DCM (100 mL) was added PBr₃ (19.22 g, 71 mmol) at 0° C.over a period of 15 min. The mixture was stirred at 0° C. for 2 h. Themixture was poured into ice-water (100 mL) and stirred for 5 min. Theaqueous phase was extracted with DCM (50 mL×2). The combined organicphase was washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (SiO₂, PE:EtOAc=100:1 to10:1) to give 1-[[1-(bromomethyl)cyclopropyl]methyl]-4-nitro-pyrazole asa white solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.24 (s, 1H), 8.11 (s,1H), 4.23, (s, 2H), 3.23, (s, 2H), 1.03-1.08 (m, 2H), 0.82-0.87 (m, 2H).

3-nitrospiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]

To a solution of 1-[[1-(bromomethyl)cyclopropyl]methyl]-4-nitro-pyrazole(560 mg, 2.15 mmol) in THF (500 mL) was added a solution of LiHMDS (4.3mmol, 1 M, 4.3 mL) dropwise at −78° C. under N₂. After addition thereaction was allowed to warm to 25° C. over a period of 2 h, and stirredat 60° C. for 4 h. The five parallel reactions were combined to workup.The mixture was quenched by aq. NH₄Cl (100 ml) and extracted with MTBE(3×100 mL). The combined organic phase was washed with brine (2×100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The product was purified by prep-HPLC (TFA) to give3-nitrospiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane] as ayellow solid. LCMS: RT 0.986 min, m/z=180 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.09 (s, 1H), 4.15 (s, 2H), 3.24 (s, 2H), 0.92 (s, 4H).

Spiro [4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine

To a solution of3-nitrospiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane] (90mg, 502 umol) in MeOH (5 mL) was added Pd/C under N₂. The suspension wasdegassed under vacuum and purged with H₂ three times. The mixture wasstirred under H₂ (20 psi) at 25° C. for 2 h. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure togive spiro [4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amineas a brown solid. LCMS: RT 0.911 min, m, =150 [M+H]⁺. ¹H NMR (400 MHz,CDCl3): δ ppm 7.24 (s, 1H), 4.01 (s, 2H), 2.81 (s, 2H), 2.72 (br. s.,1H), 0.77-0.86 (m, 4H).

N-[6-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-2-yl]spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine

To a mixture of spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine (80 mg,536.23 umol) and2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (261 mg,804.35 umol) in 1,4-dioxane (1 mL) was added XPhos (51 mg, 107.25 umol),Cs₂CO₃ (419 mg, 1.29 mmol) and Pd₂(dba)₃ (49 mg, 53.62 umol) at 20° C.under N₂. The mixture was heated to 110° C. and stirred for 5 h. Themixture was cooled to 20° C. then added with water (5 mL). The aqueousphase was extracted with EtOAc (3×3 mL). The combined organic phase waswashed with brine (3 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (PE:EtOAc=1:1) to giveN-[6-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-2-yl]spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amineas a yellow oil.

N-(6-cyclopropyl-9H-purin-2-yl)spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine

To a mixture ofN-[6-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-2-yl]spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine(230 mg, 525.58 umol) in DCM (20 mL) was added TFA (6.16 g, 54.02 mmol)in one portion at 20° C. The mixture was heated to 40° C. and stirredfor 5 h. The mixture was then cooled to 20° C. and concentrated underreduced pressure. The residue was added with THF (10 mL) and aq. K₂CO₃(10 mL) then stirred for 2 h. The mixture was filtered and the filtratewas concentrated, extracted with EtOAc (3×5 mL). The combined organicphase was washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (neutral condition) to giveN-(6-cyclopropyl-9H-purin-2-yl)spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine.LCMS: RT 0.212 min, m/z=308.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl3): δ ppm12.53 (br. s., 1H), 7.64 (s, 1H), 7.06 (s, 1H), 6.48 (s, 1H), 3.94 (s,2H), 2.77 (s, 2H), 2.60-2.69 (m, 1H), 1.36 (br. s., 2H), 1.17 (dd,J=7.53, 3.01 Hz, 2H), 0.39-0.60 (m, 4H). HPLC: RT: 1.658 min. MS: m/z:308.2 [M+H]⁺.

Example C-9 Synthesis of2-(4-((6-cyclopropyl-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(C-9) Methyl 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate

To a solution of 3-methyl-4-nitro-1H-pyrazole (40 g, 314.71 mmol) in DMF(700 mL) was added NaH (18.88 g, 472.06 mmol, 60% purity) at 0° C. overa period of 30 min under N₂. The reaction was then stirred at 25° C. for2 h followed by the addition of methyl 2-bromo-2-methylpropanoate (85.46g, 472.06 mmol, 61.04 mL) dropwise at 0° C. The reaction mixture waswarmed to 25° C. and stirred at 25° C. for another 16 h. TLC (petroleumether/ethyl acetate=5:1) showed the starting material was consumedcompletely. The reaction was quenched by ice water slowly and thenextracted with EtOAc (3×700 mL). The combined organic phase was washedwith brine (3×200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (petroleum ether/ethyl acetate=30:1-15:1), to yield thedesired product as a light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.29(s, 1H), 3.72 (s, 1H), 2.51 (s, 1H), 1.84 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid

To a mixture of methyl2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g, 306.75mmol) in THF (1 L) and H₂O (250 mL) was added LiOH.H₂O (15.45 g, 368.10mmol) at 25° C. under N₂. The mixture was then stirred at 25° C. for 16h. TLC (petroleum ether/ethyl acetate=5:1) showed the reaction wascompleted. The reaction mixture was concentrated in vacuo. The residualaqueous solution was washed with ethyl acetate (50 mL). The aqueousphase was then cooled to 0° C., adjusted to approximately pH 1-2, andfiltered to yield the desired product as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 8.65 (s, 1H), 2.48 (s, 1H), 1.83 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide

To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoicacid (25 g, 117.27 mmol) in DCM (500 mL) was added 8 drops of DMF,followed by oxalyl chloride (29.77 g, 234.54 mmol) at 0° C. under N₂.The mixture was then stirred at 25° C. for a further 2 h. TLC (petroleumether/ethyl acetate=3:1) showed reaction was completed. The reactionsolution was concentrated in vacuo. The residue solid was dissolved inTHF (300 mL) and added dropwise into a stirred solution of NH₄OH (413.61g, 11.80 mol, 454.52 mL) at 0° C. The reaction was stirred at 25° C. for1 h. TLC (ethyl acetate) showed reaction was completed. The solution wasthen concentrated in vacuo and partitioned between EtOAc (100 mL) andwater (100 mL), and the aqueous phase was extracted with ethyl acetate(3×80 mL). The combined organic phase was washed with brine (3×40 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo, toyield the desired compound as a yellow solid. ¹H NMR (400 MHz, MeOD): δ8.81 (s, 1H), 7.16-7.26 (m, 2H), 2.42 (s, 3H), 1.71 (s, 3H).

2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile

A solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22g, 103.67 mmol) in POCl₃ (132 g, 860.89 mmol, 80 mL) was stirred at 90°C. for 1 h. TLC showed the reaction was completed. The mixture wascooled to 20° C. and concentrated in vacuo at 50° C. The residue waspoured into ice-water (w/w=1/1) (200 mL) and stirred for 10 min. Theaqueous phase was adjusted to pH=7 with NaHCO₃ solution, extracted withethyl acetate (4×80 mL). The combined organic phase was washed withbrine (40 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo. The desired product was afforded as a yellow solid.

2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile

To a mixture of2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g, 51.5mmol) in EtOH (240 mL) and H₂O (60 mL) was added NH₄Cl (13.77 g, 257.5mmol) in one portion at 25° C., followed by Fe (14.38 g, 257.5 mmol).The mixture was heated to 80° C. and stirred for 1 h. TLC showed thereaction was completed. The solution was cooled to 20° C. The mixturewas extracted with ethyl acetate (3-100 mL), the combined organic layerswere washed with NaHCO₃ solution (50 mL) and brine (50 mL). The organiclayers were dried over Na₂SO₄, filtered and concentrated. The desiredproduct was afforded as a dark brown solid. ¹H NMR (400 MHz, CDCl₃): δ7.17 (s, 1H), 2.18 (s, 3H), 1.91 (s, 6H).

2-(4-((6-cyclopropyl-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

To a solution of2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (450 mg, 1.39mmol) and 2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (342mg, 2.09 mmol) in 1,4-dioxane (20 mL) was added Pd₂(dba)₃ (127 mg, 139umol), Cs₂CO₃ (1.13 g, 3.47 mmol) and X-Phos (132 mg, 278 umol) underN₂. The mixture was stirred at 110° C. for 12 h. The reaction mixturewas concentrated under reduced pressure to get a residue, which wasdiluted with H₂O (20 mL) and extracted with EtOAc (2×25 mL). Thecombined organic layers were washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-TLC (SiO₂, PE:EtOAc=3:1) to give2-(4-((6-cyclopropyl-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrileas a white solid. LCMS: RT 0.843 min, m/z=453.2 [M+H]⁺.

2-(4-((6-cyclopropyl-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

To a solution of2-(4-((6-cyclopropyl-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile(350 mg, 773.26 umol) in DCM (20 mL) was added TFA (7.05 g, 61.86 mmol)in one portion at 25° C. The mixture was heated to 40° C. and stirredfor 5 h. The reaction mixture was concentrated under reduced pressure toget a residue, which was dissolved in THF (20 mL) and added with aq.NaHCO₃ (20 mL). The mixture was stirred at 25° C. for 10 h. The mixturewas extracted with EtOAc (40 mL). The organic layer was washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to get a residue, which was purified by prep-HPLC(neutral) to give of2-(4-((6-cyclopropyl-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile.¹H NMR (400 MHz, DMSO-d6): δ12.27 (br. s, 1H), 8.44 (s, 1H), 8.13 (s,1H), 8.06 (s, 1H), 2.53-2.57 (m, 1H), 2.18 (s, 3H), 1.94 (s, 6H), 1.25(br. s., 2H), 1.12 (dd, J=7.72, 3.31 Hz, 2H). HPLC: RT: 1.87 min. MS: mz: 323.2 [M+H]⁺.

Example C-10 Synthesis of2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-10) 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (7 g, 37.23mmol) in DMF (37 mL) was added NIS (8.79 g, 39.09 mmol) in one portionat 0° C. under N₂. The mixture was stirred at 25° C. for 1.5 h. Thereaction solution was poured into ice-water (100 mL), and the resultingprecipitate was isolated by filtration. The filter cake was washed withice water (2×50 mL) and dried under reduced pressure to give2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid. LCMS:RT 0.771 min, m/z=313.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO): δ 13.12 (br. s.,1H), 7.97 (d, J=2.01 Hz, 1H).

2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

To a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5 g,15.93 mmol) in DMF (40 mL) was added NaH (764 mg, 19.11 mmol, 60%purity) in one portion at 0° C. under N₂. The mixture was stirred at 25°C. for 30 min, SEMCl (3.19 g, 19.12 mmol, 3.39 mL) was added to themixture at 0° C. and stirred for 1.5 h at 25° C. The mixture was pouredinto ice-water (40 mL), extracted with EtOAc (3×30 mL). The combinedorganic phase was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (PE:EtOAc=10:1) toafford2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silaneas a yellow solid. LCMS: RT 0.996 min, m/z=444 [M+H]⁺. ¹H NMR (400 MHz,DMSO): δ 8.15 (s, 1H), 5.55 (s, 2H), 3.49-3.56 (m, 2H), 0.81-0.87 (m,2H), −0.08 (s, 9H).

2,4-dichloro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a mixture of2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(2 g, 4.50 mmol) in NMP (32 mL) was added CuCN (806.54 mg, 9.01 mmol,1.97 mL) in one portion at 25° C. under N₂. The mixture was heated to120° C. and stirred for 4.5 h. The mixture was cooled to 25° C. andpoured into ice-water (150 mL). The aqueous phase was extracted withEtOAc (3×60 mL). The combined organic phase was washed with brine (3×60mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=15:1) to afford2,4-dichloro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a yellow solid. LCMS: RT 0.912 min, m/z=343.1 [M+H]⁺.

2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of2,4-dichloro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(1.48 g, 4.31 mmol) and cyclopropylboronic acid (630 mg, 7.33 mmol) in1,4-dioxane (30 mL) was added K₃PO₄ (2.74 g, 12.93 mmol), Ag₂O (499 mg,2.15 mmol), Pd(dppf)Cl₂ (315 mg, 431 umol) under N₂. The mixture wasstirred at 90° C. for 4.5 h. The mixture was cooled to 25° C. and pouredinto ice-water (30 mL). The aqueous phase was extracted with EtOAc (3-20mL). The combined organic phase was washed with brine (20 mL×3), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(PE:EtOAc=30:1) to afford2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a yellow solid. LCMS: RT 1.023 min, m/z=349.2 [M+H]r. ¹H NMR (400MHz, CDCl₃): δ 7.82-7.83 (m, 1H), 5.60-5.62 (m, 2H), 3.55-3.61 (m, 2H),2.73-2.81 (m, 1H), 1.45-1.48 (m, 2H), 1.30-1.34 (m, 2H), 0.92-0.97 (m,2H), −0.01 (s, 9H).

2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(100 mg, 286.62 umol) and2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (56 mg, 343.94umol) in 1,4-dioxane (10 mL) was added Pd₂(dba)₃ (26 mg, 28.66 umol),Cs₂CO₃ (233 mg, 716.55 umol) and X-Phos (27 mg, 57.32 umol) under N₂.The mixture was stirred at 110° C. for 16 h. The mixture was cooled to25° C. and poured into ice-water (16 mL). The aqueous phase wasextracted with EtOAc (3-8 mL). The combined organic phase was washedwith brine (3×8 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=5:1) to give2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a yellow solid. LCMS: RT 1.722 min, m/z=477.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 8.28-8.32 (m, 1H), 7.57 (s, 1H), 5.52 (s, 2H), 3.80 (s,1H), 3.54-3.61 (m, 2H), 2.68-2.76 (m, 1H), 2.31 (s, 3H), 2.00 (s, 6H),1.33-1.37 (m, 2H), 1.21-1.24 (m, 2H), 0.92-0.97 (m, 2H), −0.04 (s, 9H).

2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a mixture of2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(95 mg, 199.31 umol) in DCM (20 mL) was added TFA (6.16 g, 54.02 mmol, 4mL) in one portion at 0° C. under N₂. The mixture was stirred at 20° C.for 8 h. The mixture was concentrated under reduced pressure. Theresidue in THF (10 mL) was added with NaHCO₃ (12.96 g, 154.27 mmol, 6mL), stirred at 20° C. for 16 h. The mixture was poured into ice-water(10 mL). The aqueous phase was extracted with EtOAc (3×8 mL). Thecombined organic phase was washed with brine (3×8 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-HPLC (neutral condition) to provide2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile.¹H NMR (400 MHz, DMSO): δ 8.60 (br. s., 1H), 8.10 (d, J=12.80 Hz, 2H),2.17 (s, 3H), 1.94 (s, 6H), 1.15-1.25 (m, 4H). HPLC: RT: 2.498 min. MS:m/z=347.2 [M+H]⁺.

Example C-11 and C-12 Synthesis of4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-11) and4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-12)4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(300 mg, 859.85 umol), mixture of1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-amine and1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-amine (196 mg, 1.12mmol) in 1,4-dioxane (10 mL) was added Pd₂(dba)₃ (79 mg, 85.99 umol),Cs₂CO3 (700 mg, 2.15 mmol) and XPhos (82 mg, 171.97 umol). The mixturewas stirred at 110° C. for 16 h. The mixture was cooled to 20° C. andconcentrated under reduced pressure. The residue was poured intoice-water (20 mL). The aqueous phase was extracted with EtOAc (3×10 mL).The combined organic phase was washed with brine (3×10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO2, PE:EtOAc=3:1) and two productswere separated.4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrilewas obtained as a yellow oil.4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrilewas obtained as a yellow oil. LCMS: RT 0.926 min, m/z=488.3 [M+H]⁺. ¹HNMR (400 MHz, CDCl₁): δ 8.10-8.12 (m, 1H), 7.55 (s, 1H), 6.49 (s, 1H),5.50 (s, 2H), 4.87-4.93 (m, 2H), 4.77-4.82 (m, 2H), 4.13 (q, J=7.15 Hz,1H), 3.55 (t, J=8.16 Hz, 2H), 2.65-2.75 (m, 1H), 2.29 (s, 3H), 1.30-1.36(m, 2H), 1.21 (dd, J=7.53, 3.14 Hz, 2H), 0.88-0.95 (m, 2H), −0.05 (s,9H)

4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(124 mg, 254.30 umol) in DCM (20 mL) was added TFA (6.16 g, 54.03 mmol,4 mL) in one portion at 0° C. under N₂. The mixture was stirred at 20°C. for 8 h. The mixture was concentrated under reduced pressure. Theresidue in THF (10 mL) was added with aq. NaHCO₃ (12.96 g, 154.27 mmol,6 mL). The mixture was stirred at 20° C. for 16 h. The mixture waspoured into ice-water (10 mL). The aqueous phase was extracted withEtOAc (3×8 mL). The combined organic phase was washed with brine (3×8mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC (neutralcondition) to give4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile.¹H NMR (400 MHz, DMSO): δ 8.35-8.40 (m, 1H), 8.01-8.04 (m, 1H),7.63-7.67 (m, 1H), 4.89-5.02 (m, 1H), 4.85 (br. s., 2H), 4.70-4.76 (m,2H), 2.18 (s, 3H), 1.09-1.21 (m, 4H). HPLC: RT: 2.333 min. MS: m/z=358.2[M+H]⁺.

4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(209 mg, 428.61 μmol) was treated with TFA (48.87 mg, 428.61 umol, 31.73μL) in one portion at 0° C. under N₂. The mixture was stirred at 20° C.for 8 h. The mixture was concentrated under reduced pressure. Theresidue in THF (10 mL) was added with aq. NaHCO₃ (12.96 g, 154.27 mmol).The mixture was stirred at 20° C. for 16 h. The mixture was poured intoice-water (10 mL). The aqueous phase was extracted with EtOAc (3×38 mL).The combined organic phase was washed with brine (3-38 mL), dried withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-HPLC (neutral condition) to give4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile.¹H NMR (400 MHz, DMSO): δ 8.39 (br. s., 1H), 8.03 (s, 1H), 7.94 (s, 1H),4.70-4.89 (m, 5H), 2.12 (s, 3H), 1.21 (br. s., 2H), 1.14 (d, J=7.78 Hz,2H). HPLC: RT: 2.63 min. MS: m/z=358.2 [M+H]⁺.

Example C-13 Synthesis of4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-13)4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-ylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile

A mixture of spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-amine (135 mg,904.89 umol),2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(379 mg, 1.09 mmol), Cs₂CO₃ (737 mg, 2.26 mmol), Pd₂(dba)₃ (83 mg, 90.49umol) and XPhos (86 mg, 180.98 umol) in 1,4-dioxane (5 mL) was degassedand purged with N₂ for 3 times, and then the mixture was stirred at 110°C. for 16 h under N₂. The mixture was cooled to 20° C. and concentratedunder reduced pressure. The residue was poured into ice-water (5 mL).The aqueous phase was extracted with EtOAc (4 mL×3). The combinedorganic phase was washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-ylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a yellow oil. LCMS: 1.019 min, m/z=462.3 [M+H]⁺.

4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-ylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(352 mg, 762.50 umol) in DCM (20 mL) was added TFA (6.16 g, 54.02 mmol,4 mL) in one portion at 0° C. under N₂. The mixture was stirred at 20°C. for 8 h. The mixture was concentrated under reduced pressure. Theresidue in THF (20 mL) and water (4 mL) was added with K₂CO₃ (5 g, 36.18mmol). The mixture was stirred at 20° C. for 16 h. The mixture waspoured into ice-water (10 mL) and extracted with EtOAc (3×8 mL). Thecombined organic phase was washed with brine (3×8 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-HPLC (neutral condition) to give4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1′-cyclopropane]-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile.¹H NMR (400 MHz, CDCl₃): δ 11.68 (br. s., 1H), 7.63 (s, 1H), 6.71 (s,1H), 6.43 (s, 1H), 3.93 (s, 2H), 2.80 (s, 2H), 2.65-2.73 (m, 1H),1.30-1.35 (m, 2H), 1.16-1.22 (m, 2H), 0.60-0.65 (m, 2H), 0.48-0.53 (m,2H). HPLC: RT: 2.402 min. MS: m/z=332.2 [M+H]⁺.

Example C-14 Synthesis of2-[4-[(4-cyclopropyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(C-14) 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (50 g, 0.27mol) in CH₃CN (1 L) and AcOH (200 mL) was added selectfluor (131.9 g,0.37 mol) in one portion. The reaction mixture was stirred at 60° C. for12 h under Ar. The reaction mixture was poured into cold water (1 L) andcrystallized for 30 min, filtrated to give2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine as a brown solid.LCMS: RT 1.268 min, m/z=206.0 [M+H]⁺.

2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (2.17g, 10.53 mmol) in DMF (22 mL) was added NaH (843 mg, 21.06 mmol, 60%purity) at 0° C., then the mixture was warmed to 25° C. and stirred for30 min. A solution of SEMCl (1.84 g, 11.06 mmol, 1.96 mL) in DMF (10 mL)was added dropwise to the mixture and stirred continuously for 3 h. Thereaction mixture was quenched by pouring into ice water (150 mL). Theresulting aqueous layer was extracted with EtOAc (3×100 mL). Thecombined organics were washed with brine (two times) and dried overNa₂SO₄, concentrated under reduced pressure to give a residue, which waspurified with a short silica gel plug eluting with PE:EtOAc=200:1 to50:1 to give2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidineas a yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d): δ7.17 (d, J=2.8 Hz,1H), 5.61 (s, 2H), 3.50-3.63 (m, 2H), 0.94-1.01 (m, 2H), −0.02-0.03 (m,9H).

2-[(2-chloro-4-cyclopropyl-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

To a mixture of2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(2.9 g, 8.62 mmol) and cyclopropylboronic acid (1.26 g, 14.65 mmol) in1,4-dioxane (40 mL) was added Ag₂O (999 mg, 4.31 mmol), Pd(dppf)Cl₂ (631mg, 862 umol) and K₃PO₄ (5.49 g, 25.86 mmol) at 20° C. under N₂. Themixture was stirred at 90° C. for 4.5 h, then cooled to 20° C. andpoured into ice-water (80 mL). The aqueous phase was extracted withEtOAc (40 mL×3). The combined organic phase was washed with brine (40mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=30:1) to give2-[(2-chloro-4-cyclopropyl-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silaneas a yellow solid. LCMS: RT 1.006 min, m/z=342.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 6.99 (d, J=2.51 Hz, 1H), 5.53 (s, 2H), 3.48-3.54 (m, 2H),2.48-2.56 (m, 1H), 1.40-1.44 (m, 2H), 1.19-1.25 (m, 2H), 0.90-0.94 (m,2H), −0.03 (s, 9H).

2-[4-[[4-cyclopropyl-5-fluoro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

A mixture of2-[(2-chloro-4-cyclopropyl-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(200 mg, 585 umol),2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (134 mg,819.00 μmol), Pd₂(dba)₃ (54 mg, 58.50 μmol), XPhos (56 mg, 117 μmol) andCs₂CO₃ (477 mg, 1.46 mmol) in 1,4-dioxane (15 mL) was degassed andpurged with N₂ for 3 times, then the mixture was stirred at 110° C. for16 h under N₂. The mixture was cooled to 20° C. and poured intoice-water (30 mL). The aqueous phase was extracted with EtOAc (3×15 mL).The combined organic phase was washed with brine (15 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, PE:EtOAc=3:1) to give2-[4-[[4-cyclopropyl-5-fluoro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrileas a yellow oil. LCMS: RT 1.005 min, m, =470.3 [M+H]⁺.

2-[4-[(4-cyclopropyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a solution of2-[4-[[4-cyclopropyl-5-fluoro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(169 mg, 359.86 μmol) in DCM (20 mL) was added SnCl₄ (1.22 g, 4.68 mmol,546.53 uL) at 0° C. under N₂. The mixture was stirred at 20° C. for 4 h,poured into ice-water (10 mL). The mixture was neutralized with aq.NaHCO₃ (21.6 g, 257.11 mmol, 10 mL) to pH=8. The mixture was extractedwith EtOAc (3×10 mL). The combined organic phase was washed with brine(10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. To a solution of the residue in THF (20 mL) and Water(4 mL) was added K₂CO₃ (3.00 g, 21.71 mmol), and the mixture stirred at20° C. for 16 h. The reaction mixture was poured into ice-water (10 mL)and extracted with EtOAc (3×10 mL). The combined organic phase waswashed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral condition) to give2-[4-[(4-cyclopropyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile.¹H NMR (400 MHz, CDCl₃): δ 8.26-8.32 (m, 1H), 8.18 (s, 1H), 6.58 (t,J=2.45 Hz, 1H), 6.38 (s, 1H), 2.44-2.53 (m, 1H), 2.29 (s, 3H), 1.97 (s,6H), 1.31-1.36 (m, 2H), 1.11-1.18 (m, 2H). HPLC: RT: 2.731 min. MS:m/z=340.2 [M+H]⁺.

Example C-15 and C-16 Synthesis of4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-15) and4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-16)2,4-dichloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g,22.5 mmol) in THF (400 mL) was added LDA (113 mL, 0.23 mol, 2M) at −78°C., the mixture was stirred at −20° C. for 2 h. Then re-cooled to −78°C., to the reaction solution was added CH₃I (32 g, 225.1 mmol, 14 mL),then the mixture stirred at −20° C. for 2 h. The reaction mixture wasquenched with sat. NH₄Cl (300 mL), and extracted with EtOAc (3×300 mL).The combined organic phase was washed with brine (3×200 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by silica gel column chromatography(PE:EtOAc=10:1) to give2,4-dichloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidineas a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d: δ 5.59-5.67 (m, 2H),3.47-3.56 (m, 2H), 2.57 (s, 3H), 0.89-0.96 (m, 2H), −0.03 (s, 9H).

2,4-dichloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of2,4-dichloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(5 g, 10.9 mmol) in NMP (50 mL) was added CuCN (1.95 g, 21.8 mmol) at25° C. under N₂. The reaction mixture was heated to 120° C. and stirredfor 12 h. Then the reaction was poured into ice-water (200 mL), andextracted with EtOAc (3×200 mL). The combined organic phase was washedwith brine (200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=10:1) to give2,4-dichloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a yellow oil. LCMS: RT 1.006 min, m/z=357.2 [M+H]⁺.

2-chloro-4-cyclopropyl-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of2,4-dichloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(300 mg, 0.84 mmol) and cyclopropylboronic acid (87 mg, 1.01 mmol) indioxane (2 mL) was added K₃PO₄ (535 mg, 2.52 mmol), Ag₂O (98 mg, 0.42mmol) and Pd(dppf)Cl₂ (61 mg, 84 umol) under N₂. The reaction mixturewas stirred at 90° C. for 12 h. The mixture was cooled to 20° C. andpoured into ice-water (w/w=1/1) (2 mL). The aqueous phase was extractedwith EtOAc (3×2 mL). The combined organic phase was washed with brine (2mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue, which was purified by silica gelcolumn chromatography (PE:EtOAc=1:1) to give2-chloro-4-cyclopropyl-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a brown oil. LCMS: RT 1.05 min, m/z=363.1 [M+H]⁺.

4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of2-chloro-4-cyclopropyl-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(200 mg, 0.55 mmol) in 1, 4-dioxane (4 mL) was added a mixture of1,3-dimethyl-1H-pyrazol-4-amine and 1,5-dimethyl-1H-pyrazol-4-amine (49mg, 0.44 mmol), Cs₂CO₃ (450 mg, 1.38 mmol), XPhos (53 mg, 0.11 umol) andPd₂(dba)₃ (51 mg, 55 umol) under N₂, then the mixture was stirred at110° C. for 12 h. The reaction mixture was concentrated under reducedpressure to give residue, which was purified by prep-TLC (SiO₂,PE:EtOAc=1:1) to give a mixture of compound4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a yellow oil. MS: m/z=438.2 [M+H]⁺.

4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of mixture of4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(70 mg, 0.16 mmol) in DCM (4 mL) was added TFA (365 mg, 0.24 mL, 3.2mmol) at 0° C., then the mixture was stirred at 40° C. for 24 h. Thereaction mixture was concentrated under reduced pressure to give ayellow oil. LCMS: RT 1.075 min, m/z=338.2 [M+H]⁺. To a solution of thiscrude material in THF (4 mL) and water (4 mL) was added K₂CO₃ (225 mg,1.63 mmol) at 20° C. Then the mixture was stirred at 50° C. for 4 h. Themixture was concentrated under reduced pressure to give a residue, whichwas purified by prep-HPLC (FA) to give4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile.

4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (br. s., 1H), 8.25 (s, 1H), 7.69 (s,1H), 3.68-3.73 (m, 3H), 2.43 (s, 4H), 2.05 (s, 3H), 1.16 (d, J=4.0 Hz,2H), 1.06-1.12 (m, 2H). HPLC: RT: 2.34 min. MS: m/z: 308.1 [M+H]⁺.

4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

¹H NMR (400 MHz, DMSO-d6): δ 12.19 (br. s., 1H), 8.21 (s, 1H), 7.42 (s,1H), 3.68 (s, 3H), 2.42 (s, 4H), 2.11 (s, 3H), 1.13 (br. s., 2H), 1.09(d, J=7.94 Hz, 2H). HPLC: RT: 2.25 min. MS: m/z: 308.2 [M+H]⁺.

Example C-17 Synthesis of7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine(C-17) 4-chloropyridine-2,3-diamine

To a solution of 4-chloropyridine-2,3-diamine (6 g, 34.57 mmol) ini-PrOH (60 mL) and H₂O (15 mL) was added Fe (9.65 g, 172.85 mmol) andNH₄Cl (9.25 g, 172.85 mmol). The mixture was stirred at 80° C. for 2 h.The reaction mixture was filtered and to the filtrate was added H₂O (100mL) at 0° C. Then it was extracted with DCM/i-PrOH (60 mL×4). Thecombined organic layers were washed with brine (60 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give4-chloropyridine-2,3-diamine as a dark brown solid. LCMS: RT 0.107 min,m/z=144.1 [M+H]⁺.

7-chloro-3H-imidazo[4,5-b]pyridine

A solution of 4-chloropyridine-2,3-diamine (I g, 6.97 mmol) in CH(OEt)₃(20 mL) and HCOOH (0.5 mL) was degassed and purged with N₂ for 3 times,and then the mixture was stirred at 100° C. for 3 h under N₂. Thereaction mixture was concentrated under reduced pressure. The residuewas diluted with water (20 mL) and extracted with DCM/i-PrOH (20 mL×3).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give7-chloro-3H-imidazo[4,5-b]pyridine as a dark brown solid. LCMS: RT 0.140min, m/z=154.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 13.43 (br. s, 1H),8.52 (d, J=5.14 Hz, 1H), 8.29 (d, J=5.14 Hz, 1H), 7.39 (d, J=5.15 Hz,1H).

7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of 7-chloro-3H-imidazo[4,5-b]pyridine (1 g, 6.51 mmol) inDMF (10 mL) was added NaH (312 mg, 7.81 mmol, 60% purity) in threeportions at 0° C. The mixture was stirred at 20° C. for 1 h. SEM-Cl (1.3g, 7.81 mmol, 1.39 mL) was added at 0° C. and the mixture was stirred at20° C. for 1 h. The reaction mixture was quenched by addition of water(60 mL) at 0° C., and then extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine (20 mL×3), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue,which was purified by silica gel column chromatography (PE:EtOAc=6:1) togive7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridineas a yellow oil. LCMS: RT 0.901 min, m/z=284.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl3): δ 8.32 (d, J=5.27 Hz, 1H), 8.24 (s, 1H), 7.32 (d, J=5.27 Hz,1H), 5.69 (s, 2H), 3.58-3.66 (m, 2H), 0.91-0.96 (m, 2H), −0.04 (s, 9H).

7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine

A mixture of cyclopropylboronic acid (181 mg, 2.12 mmol),7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine(400 mg, 1.41 mmol), Cs₂CO₃ (918 mg, 2.82 mmol), Pd₂(dba)₃ (64 mg, 70.5umol) and DavePhos (55 mg, 141 umol) in toluene (20 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 120° C.for 3 h under N₂. The reaction mixture was concentrated under reducedpressure to give a residue, which was purified by silica gel columnchromatography (PE:EtOAc=8:1) to give7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine.LCMS: RT 0.835 min, m/z=290.1 [M+H]⁺.

7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine4-oxide

To a solution of7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine(6.7 g, 23.15 mmol) in CHCl₃ (70 mL) was added m-CPBA (9.4 g, 46.3 mmol,85% purity). The mixture was stirred at 75° C. for 16 h. The reactionmixture was quenched by addition of H₂O (120 mL) and Na₂S₂O₃ (12 g) at0° C., and then extracted with DCM (50 mL×3). The combined organiclayers were washed with saturated NaHCO₃ solution (60 mL) and brine (60mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue, which was purified by silica gel columnchromatography (DCM:MeOH=10:1) to give7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine4-oxide as a dark brown gum. LCMS: RT 0.765 min, m/z=306.2 [M+H]⁺

5-chloro-7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine(Intermediate 15)

To a solution of7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine4-oxide (3 g, 9.82 mmol) in DMF (30 mL) was added MsCl (4.50 g, 39.29mmol, 3.04 mL). The mixture was stirred at 80° C. for 20 min. Thereaction mixture was quenched by addition of H₂O (180 mL) at 0° C.,alkalified with aq. NaHCO₃ to pH=8 and extracted with EtOAc (60 mL×3).The combined organic layers were washed with brine (3×30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give5-chloro-7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine.LCMS: RT 0.953 min, m/z=324.1[M+H]⁺.

7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-amine

A mixture of5-chloro-7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine(170 mg, 524.87 umol), 1-methylpyrazol-3-amine (102 mg, 1.05 mmol),Cs₂CO₃ (427 mg, 1.31 mmol), Pd₂(dba)₃ (48 mg, 52.49 umol) and XPhos (50mg, 104.97 umol) in 1,4-dioxane (4 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 110° C. for 16 h underN₂. The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with H₂O (20 mL) and extracted with DCM (3×10 mL).The combined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-TLC (SiO₂, EtOAc) to give7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-amineas a yellow gum. LCMS: RT 0.832 min, m/z=385.3 [M+H]⁺.

7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine)

To a solution of7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-amine(80 mg, 208.04 umol) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3mL). The mixture was stirred at 40° C. for 6 h. The reaction mixture wasconcentrated under reduced pressure to get a residue, which was purifiedby prep-HPLC (neutral condition) to give7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine.¹H NMR (400 MHz, CDCl₃): δ 7.89 (s, 1H), 7.33 (d, J=2.26 Hz, 1H), 6.62(s, 1H), 6.27 (d, J=2.26 Hz, 1H), 3.94 (s, 3H), 2.44-2.54 (m, 1H),1.15-1.20 (m, 4H). HPLC: RT: 2.65 min. MS: m/z: 255.1 [M+H]⁺.

Example C-18 and C-19 Synthesis of4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-18) and4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(C-19)4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a mixture of2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(400 mg, 1.15 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine and1,5-dimethyl-1H-pyrazol-4-amine (217 mg, 1.95 mmol, mixture) in1,4-dioxane (15 mL) was added Pd₂(dba)₃ (105 mg, 115 umol) in oneportion at 20° C. under N₂. The mixture was heated to 110° C. andstirred for 16 h, cooled to 20° C. and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=1:1) to afford4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrileas a yellow oil. LCMS: RT 1.589 min, m/z=424.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 7.81 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 5.51(s, 1H), 5.46 (s, 2H), 3.86 (s, 2H), 3.79-3.83 (m, 3H), 3.54 (dt,J=12.05, 8.22 Hz, 4H), 2.63-2.74 (m, 2H), 2.27 (s, 2H), 2.22 (s, 3H),1.13-1.22 (m, 4H), 0.91 (dt, J=11.45, 8.27 Hz, 4H), −0.05 (s, 9H).

4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrileand4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

To a solution of4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile(297 mg, 701.15 umol, mixture) and4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrilein DCM (20 mL) was added TFA (6.16 g, 54.03 mmol, 4 mL) in one portionat 0° C. under N₂. The mixture was stirred at 20° C. for 8 h. Themixture was concentrated under reduced pressure. The residue in THF (10mL) was added with aq. NaHCO₃ (12.96 g, 154.27 mmol, 6 mL). The mixturewas stirred at 20° C. for 16 h, and poured into ice-water (10 mL) andextracted with EtOAc (3×8 mL). The combined organic phase was washedwith brine (3×8 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (FA condition) to provide4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrilewas as a white solid and4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile.

4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

¹H NMR (400 MHz, DMSO): δ 12.29 (br. s., 1H), 8.30 (s, 1H), 8.01 (s,1H), 7.44 (s, 1H), 3.69 (s, 3H), 2.12 (s, 3H), 1.10-1.20 (m, 4H). HPLC:RT: 2.17 min. MS: m/z=294.2 [M+H]⁺.

4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

¹H NMR (400 MHz, DMSO): δ 12.31 (br. s., 1H), 8.34 (s, 1H), 8.03 (s,1H), 7.72 (s, 1H), 3.72 (s, 3H), 2.07 (s, 3H), 1.20 (br. s., 2H), 1.14(d, J=7.40 Hz, 2H). HPLC: RT: 2.20 min. MS: m/z=294.2 [M+H]⁺.

Example C-20 Synthesis of4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(C-20) 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine

To a solution of 4-chloro-7-azaindole (20 g, 131.08 mmol) in AcOH (200mL) was added NIS (30.96 g, 137.63 mmol) in portions at 0° C. under N₂.The mixture was stirred at 20° C. for 16 h. The reaction mixture wasdiluted with water (500 mL) and extracted with DCM (3×400 mL). Thecombined organic layers were washed with saturated aq. NaHCO₃ (300 mL)and brine (400 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine as ablack brown solid crude material. LCMS: RT 0.83 min, m/z=279.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6): δ 12.53 (br. s., 1H), 8.18 (d, J=5.14 Hz,1H), 7.79 (d, J=2.13 Hz, 1H), 7.18 (d, J=5.02 Hz, 1H).

4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (50 g, 179.55mmol) in DMF (500 mL) was added NaH (8.62 g, 215.46 mmol, 60% purity) inportions at 0° C. under N₂. The mixture was stirred at 20° C. for 1 h.Then SEM-Cl (35.92 g, 215.46 mmol) was added to the mixture and stirredat 20° C. for 2 h. The mixture was poured into ice-water (1000 mL) andstirred for 5 min. The aqueous phase was extracted with ethyl acetate(3×500 mL). The combined organic phase was washed with brine (3-500 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue, which was purified by silica gel columnchromatography (PE:EtOAc=20:1) to give4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridineas a black brown solid.

4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

A mixture of4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(3 g, 7.34 mmol) and CuCN (1.31 g, 14.68 mmol) in NMP (20 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 120° C. for 4.5 h under N₂ atmosphere. The mixture was cooledto 20° C. and poured into ice-water (20 mL). The aqueous phase wasextracted with ethyl acetate (3×15 mL). The combined organic phase waswashed with brine (3×15 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated to give a residue, which was purified by silica gel columnchromatography (PE:EtOAc=15:1) to afford4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a yellow solid. LCMS: RT 0.938 min, m/z=308.1 [M+H]⁺.

4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

A mixture of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(1.03 g, 3.35 mmol), cyclopropylboronic acid (575 mg, 6.70 mmol),Pd₂(dba)₃ (460 mg, 502.50 umol), Cs₂CO₃ (2.18 g, 6.70 mmol) and DavePhos(132 mg, 335 umol) in toluene (15 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 120° C. for 8 h underN₂. The mixture was concentrated under reduced pressure to give aresidue, which was purified by silica gel column chromatography(PE:EtOAc=30:1) to give4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a yellow solid. LCMS: RT 0.937 min, m/z=314.2 [M+H]⁺.

3-cyano-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine7-oxide

To a solution of4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(3.3 g, 10.53 mmol) in CHCl₃ (40 mL) was added m-CPBA (6.41 g, 31.59mmol, 85% purity). The mixture was stirred at 75° C. for 16 h. Thereaction mixture was quenched by addition of water (150 mL) and Na₂S₂O₃(8 g) at 0° C., and then extracted with DCM (3×50 mL). The combinedorganic layers were washed with saturated NaHCO₃ solution (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue, which was purified by silica gelcolumn chromatography (DCM:MeOH=10:1) to give3-cyano-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine7-oxide as a white solid. LCMS: RT 1.015 min, m/z=330.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): δ 8.09 (d, J=6.53 Hz, 1H), 7.87 (s, 1H), 6.67 (d.J=6.53 Hz, 1H), 6.35 (s, 2H), 3.65-3.73 (m, 2H), 2.57-2.68 (m, 1H),1.23-1.28 (m, 2H), 0.93-0.98 (m, 2H), 0.87-0.92 (m, 2H), −0.02 (s, 9H).

6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of3-cyano-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine7-oxide (1.78 g, 5.40 mmol) in DMF (18 mL) was added MsCl (2.47 g, 21.60mmol) and the mixture was stirred at 80° C. for 20 min. The reactionmixture was quenched by addition H₂O (120 mL) at 0° C. and treated withsaturated aq. NaHCO₃ solution to pH=8 and extracted with EtOAc (3×40mL). The combined organic layers were washed with brine (3×30 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a black brown gum. LCMS: RT 1.004 min, m/z=348.1 [M+H]⁺.

3-iodo-1,4-dimethyl-pyrazole

To a solution of 1,4-dimethyl-pyrazole (10 g, 104.03 mmol) in DMF (150mL) was added NIS (21.06 g, 93.63 mmol) in one portion at 25° C. underN₂. The mixture was stirred at 60° C. for 12 h. The mixture was pouredinto ice-water (300 mL) and stirred for 5 min. The aqueous phase wasextracted with MTBE (3×300 mL). The combined organic phase was washedwith brine (3×200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=10:1-1:1) to give3-iodo-1,4-dimethyl-pyrazole as a brown solid. ¹H NMR (400 MHz, CDCl₃):δ ppm 7.05 (s, 1H), 3.86 (s, 3H), 1.98 (s, 3H).

Tert-butyl N-(1,4-dimethylpyrazol-3-yl)carbamate

A mixture of 3-iodo-1,4-dimethyl-pyrazole (5 g, 22.52 mmol), tert-butylcarbamate (3.43 g, 29.28 mmol), CuI (2.14 g, 11.26 mmol), K₂CO₃ (6.22 g,45.04 mmol) and (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (1.6 g,11.26 mmol) in 1,4-dioxane (60 mL) was degassed and purged with N₂ for 3times, and then the mixture solution was stirred at 110° C. for 12 hunder N₂. To the reaction solution was added water (80 mL), extractedwith EtOAc (30 mL×3), organic layers were combined, washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=5:1 to 3:1) to give tert-butylN-(1,4-dimethylpyrazol-3-yl)carbamate as a light brown solid. ¹H NMR(400 MHz, CDCl₃): δ ppm 7.06 (s, 1H), 6.44 (br. s., 1H), 3.71-3.81 (m,3H), 1.98 (s, 3H), 1.48 (s, 9H).

1,4-dimethylpyrazol-3-amine

To a mixture of tert-butyl N-(1,4-dimethylpyrazol-3-yl)carbamate (700mg, 3.31 mmol) in 1,4-dioxane (10 mL) was added HCl/dioxane (15 mL) at20° C. The mixture was stirred at 20° C. for 5 h. The mixture wasconcentrated under reduced pressure to give 1,4-dimethylpyrazol-3-amine(HCl salt) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.21 (br.s., 2H), 7.58 (s, 1H), 3.74 (s, 3H), 3.39 (s, 1H), 1.98 (s, 3H).

4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

A mixture of6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(250 mg, 718.56 umol), 1,4-dimethylpyrazol-3-amine (160 mg, 1.44 mmol),Cs₂CO₃ (1.05 g, 3.23 mmol), Pd₂(dba)₃ (66 mg, 71.86 umol) and XPhos (68mg, 143.71 umol) in 1,4-dioxane (6 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 110° C. for 16 h underN₂. The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with H₂O (60 mL) and extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a yellow gum. LCMS: RT 0.902 min, m/z=423.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl3): δ ppm 7.59 (s, 1H), 7.12 (s, 1H), 6.69 (s, 1H), 6.33 (s, 1H),5.54 (s, 2H), 3.82 (s, 3H), 3.53-3.58 (m, 2H), 2.52-2.64 (m, 1H), 1.96(s, 3H), 1.14 (dd, J=8.34, 2.07 Hz, 2H), 0.90-0.95 (m, 2H), 0.86 (dd,J=4.77, 1.63 Hz, 2H), −0.03 (s, 9H).

4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(210 mg, 496.92 umol) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3mL). The mixture was stirred at 40° C. for 6 h and concentrated underreduced pressure to get a residue. K₂CO₃ (15 g, 108.53 mmol) was addedto the residue in THF (12 mL) and water (12 mL). The mixture was stirredat 40° C. for 16 h. The mixture was poured into ice-water (30 mL) andextracted with EtOAc (10 mL×3). The combined organic phase was washedwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was triturated withCH₃CN to give4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.¹H NMR (400 MHz, MeOD): δ 7.70 (s, 1H), 7.33 (s, 1H), 6.35 (s, 1H) 3.78(s, 3H), 2.47-2.55 (m, 1H), 1.92 (s, 3H), 1.09-1.15 (m, 2H), 0.79-0.85(m, 2H). HPLC: RT 2.22 min. MS: m/s: 293.1 [M+H]⁺.

Example C-21 Synthesis of4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(C-21)4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

A mixture of6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(250 mg, 718.56 umol), 1-methylpyrazol-3-amine (70 mg, 718.56 umol),Cs₂CO3 (585 mg, 1.80 mmol), Pd₂(dba)₃ (66 mg, 71.86 umol) and XPhos (68mg, 143.71 umol) in 1,4-dioxane (4 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 110° C. for 16 h underN₂. The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with H₂O (20 mL) and extracted with DCM (3×10 mL).The combined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-TLC (SiO₂, PE:EtOAc=1:1). LCMS: RT0.974 min, m/z=409.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.60 (s, 1H),6.92 (s, 1H), 6.51 (d, J=1.76 Hz, 1H), 6.39 (s, 1H), 5.58 (s, 2H), 3.83(s, 3H), 3.53-3.60 (m, 2H), 2.53-2.61 (m, 1H), 1.17 (dd, J=8.16, 1.98Hz, 2H), 0.90-0.94 (m, 2H), 0.87 (dd, J=4.85, 1.76 Hz, 2H), −0.06 (s,9H).

4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(200 mg, 489.51 umol) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3mL). The mixture was stirred at 40° C. for 4 h. The mixture wasconcentrated under reduced pressure to give a residue. K₂CO₃ (15 g,108.53 mmol) was added to the residue in THF (10 mL) and water (10 mL)and stirred at 40° C. for 16 h. The mixture was poured into ice-water(30 mL) and extracted with EtOAc (10 mL×3). The combined organic phasewas washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral condition) to give4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.¹H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 7.95 (s, 1H), 7.50 (d, J=2.13Hz, 1H), 6.56 (d, J=2.13 Hz, 1H), 6.53 (s, 1H), 3.72 (s, 3H), 2.37-2.44(m, 1H) 1.06-1.14 (m, 2H), 0.77 (dd, J=4.89, 2.01 Hz, 2H). HPLC: RT:2.12 min. MS: m/z=279.1 [M+H]⁺.

The following compounds were prepared according to the Examples aboveand/or general procedures described herein.

No. [M + H]⁺ C-22 356.1 C-23 322.2 C-24 269.1 C-25 269.1 C-26 403.2 C-27378.2 C-28 412.2 C-29 396.2 C-30 333.2 C-31 333.2 C-32 367.1 C-33 284.1C-34 284.1 C-35 269.1 C-36 310.2 C-37 378.2 C-38 330.1 C-39 330.1 C-40330.1 C-41 362.2 C-42 390.1 C-43 360.1 C-44 360.2 C-45 334.1 = [M − H]⁻C-46 336.2 C-52 310.1 C-53 319.1 C-54 319.1 C-55 367.1

D: Compound Preparation

In the following examples, all non-aqueous reactions were carried out inoven-dried or flame-dried glassware under nitrogen atmosphere. Allchemicals were purchased from commercial vendors and used as is, unlessotherwise specified. Reactions were magnetically stirred and monitoredby thin layer chromatography (TLC) with 250 μm pre-coated silica gelplates, visualized either with UV, or in an iodine chamber. Flash columnchromatography was performed using silica gel (100-200 mesh). Chemicalshifts are reported relative to chloroform (87.26), methanol (63.31), orDMSO (82.50) for ¹H NMR. HPLC analysis was performed on Shimadzu 20ABHPLC system with a photodiode array detector and Luna-C18(2) 2.0-50 mm,5 um column at a flow rate of 1.2 mL/min with a gradient solvent Mobilephase A (MPA, H₂O+0.037% (v/v) TFA): Mobile phase B (MPB. ACN+0.018%(v/v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92min, 10% MPB: 5.5 min, 10% MPB). LCMS was detected under 220 and 254 nmor used evaporative light scattering (ELSD) detection as well aspositive electrospray ionization (MS). Semi-preparative HPLC wasperformed by either acidic or neutral condition. Acidic: Luna C18 100×30mm, 5 μm; MPA: HCl/H₂O=0.04%, or formic acid/H₂O=0.2% (v/v); MPB: ACN.Neutral: Waters Xbridge 150×25, 5 μm; MPA: 10 mM NH₄HCO: in H₂O; MPB:ACN. Gradient for both conditions: 10% of MPB to 80% of MPB within 12min at a flow rate of 20 mL/min, then 100% MPB over 2 min, 10% MPB over2 min, UV detector. SFC analysis was performed on Thar analytical SFCsystem with a UV/Vis detector and series of chiral columns includingAD-3, AS-H, OJ-3, OD-3. AY-3 and IC-3, 4.6×100 mm, 3 um column at a flowrate of 4 mL/min with a gradient solvent Mobile phase A (MPA, CO₂):Mobile phase B (MPB, MeOH+0.05% (v/v) IPAm) (0.01 min, 10% MPB; 3 min,40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB). SFC preparative wasperformed on Thar 80 preparative SFC system with a UV/Vis detector andseries of chiral preparative columns including AD-H, AS-H, OJ-H, OD-H,AY-H and IC-H, 30×250 mm, Sum column at a flow rate of 65 mL/min with agradient solvent Mobile phase A (MPA, CO₂): Mobile phase B (MPB,MeOH+0.1% (v/v) NH₃H₂O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40%MPB; 6.1-10 min, 10% MPB).

Compounds were named by using either ChemBioDraw Ultra 13.0 or Chemaxon.

Example D-1 Synthesis of2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]propanenitrile(D-46) Methyl 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate

To a solution of 3-methyl-4-nitro-1H-pyrazole (1-1, 40 g, 314.71 mmol)in DMF (700 mL) was added NaH (18.88 g, 472.06 mmol, 60% purity) at 0°C. over a period of 30 min under N₂. The reaction was then stirred at25° C. for 2 h followed by the addition of methyl2-bromo-2-methylpropanoate (85.46 g, 472.06 mmol, 61.04 mL) dropwise at0° C. The reaction mixture was warmed to 25° C. and stirred at 25° C.for another 16 h. TLC (petroleum ether/ethyl acetate=5:1) showed thestarting material was consumed completely. The reaction was quenched byice water slowly and then extracted with EtOAc (3×700 mL). The combinedorganic phase was washed with brine (3×200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (petroleum ether/ethylacetate=30:1-15:1), to yield the desired product as a light yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 8.29 (s, 1H), 3.72 (s, 1H), 2.51 (s,1H), 1.84 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid

To a mixture of methyl2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g, 306.75mmol) in THF (1 L) and H₂O (250 mL) was added LiOH H₂O (15.45 g, 368.10mmol) at 25° C. under N₂. The mixture was then stirred at 25° C. for 16h. TLC (petroleum ether/ethyl acetate=5:1) showed the reaction wascompleted. The reaction mixture was concentrated in vacuo. The residualaqueous solution was washed with ethyl acetate (50 mL). The aqueousphase was then cooled to 0° C., adjusted to approximately pH 1-2, andfiltered to yield the desired product as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 8.65 (s, 1H), 2.48 (s, 1H), 1.83 (s, 6H).

2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide

To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoicacid (25 g, 117.27 mmol) in DCM (500 mL) was added 8 drops of DMF,followed by oxalyl chloride (29.77 g, 234.54 mmol) at 0° C. under N₂.The mixture was then stirred at 25° C. for a further 2 h. TLC (petroleumether/ethyl acetate=3:1) showed reaction was completed. The reactionsolution was concentrated in vacuo. The residue solid was dissolved inTHF (300 mL) and added dropwise into a stirred solution of NH₄OH (413.61g, 11.80 mol, 454.52 mL) at 0° C. The reaction was stirred at 25° C. for1 h. TLC (ethyl acetate) showed reaction was completed. The solution wasthen concentrated in vacuo and partitioned between EtOAc (100 mL) andwater (100 mL), and the aqueous phase was extracted with ethyl acetate(3×80 mL). The combined organic phase was washed with brine (3×40 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo, toyield the desired compound as a yellow solid. ¹H NMR (400 MHz, MeOD): δ8.81 (s, 1H), 7.16-7.26 (m, 2H), 2.42 (s, 3H), 1.71 (s, 3H).

2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile

A solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22g, 103.67 mmol) in POCl₃ (132 g, 860.89 mmol, 80 mL) was stirred at 90°C. for 1 h. TLC showed the reaction was completed. The mixture wascooled to 20° C. and concentrated in vacuo at 50° C. The residue waspoured into ice water (w/w=1/1) (200 mL) and stirred for 10 min. Theaqueous phase was adjusted to pH=7 with NaHCO₃ solution, extracted withethyl acetate (4×80 mL). The combined organic phase was washed withbrine (40 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo. The desired product was afforded as a yellow solid.

2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile

To a mixture of2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g, 51.5mmol) in EtOH (240 mL) and H₂O (60 mL) was added NH₄Cl (13.77 g, 257.5mmol) in one portion at 25° C., followed by Fe (14.38 g, 257.5 mmol).The mixture was heated to 80° C. and stirred for 1 h. TLC showed thereaction was completed. The solution was cooled to 20° C. The mixturewas extracted with ethyl acetate (3×100 mL), the combined organic layerswere washed with NaHCO₃ solution (50 mL) and brine (50 mL). The organiclayers were dried over Na₂SO₄, filtered and concentrated. The desiredproduct was afforded as a dark brown solid. ¹H NMR (400 MHz, CDCl₃): δ7.17 (s, 1H), 2.18 (s, 3H), 1.91 (s, 6H).

2-chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidine and4-chloro-2-methylsulfanyl-5-(trifluoromethyl)pyrimidine

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1-6, 1 g,4.61 mmol) in THF (10 mL) was added a solution of NaSMe (2.42 g, 6.92mmol, 2.20 mL) dropwise at −25° C. under N₂. The reaction mixture wasthen stirred at −25° C. for 1 hour followed by stirred at 25° C. for 15h. The reaction mixture was diluted with CH₂Cl₂ (20 mL) and washed with1 N HCl (3×10 mL). The organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated to afford a mixture of2-chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidine and4-chloro-2-methylsulfanyl-5-(trifluoromethyl)pyrimidine as yellow oil.

2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]propanenitrileand2-methyl-2-[3-methyl-4-[[2-methylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]pyrazol-1-yl]propanenitrile

To a mixture of 2-chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidineand 4-chloro-2-methylsulfanyl-5-(trifluoromethyl)pyrimidine (150 mg,656.12 μmol) in n-BuOH (3 mL) was added2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (161 mg,984.18 μmol) and TEA (99 mg, 984.18 μmol) at 25° C. under N₂. Themixture was then heated under microwave at 120° C. and stirred for 1 h.The mixture was cooled to 25° C. poured into water (10 mL) and extractedwith ethyl acetate (3-10 mL). The combined organic phase was washed withbrine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The residue was purified by prep-HPLC (HCl) to give2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]propanenitrileand2-methyl-2-[3-methyl-4-[[2-methylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]pyrazol-1-yl]propanenitrile.

2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]propanenitrile(D-46)

¹H NMR (400 MHz, CDCl₃): δ 9.45 (br. s., 1H), 8.18 (br. s., 2H), 2.68(br. s., 3H), 2.35 (br. s., 3H), 1.88-2.02 (m, 6H); HPLC: RT 3.48 min;MS: m/z: 357.1 [M+H]⁺.

2-methyl-2-[3-methyl-4-[[2-methylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]pyrazol-1-yl]propanenitrile

¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.41 (s, 1H), 8.09 (s, 1H),2.33 (s, 3H), 2.06 (s, 3H), 1.94 (s, 6H); HPLC: RT 3.19 min: MS: m/z:357.1 [M+H]⁺.

Example D-2 Synthesis of2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfanyl-pyrimidine-5-carbonitrile(D-47) 2-chloro-4-ethylsulfanyl-pyrimidine-5-carbonitrile and4-chloro-2-ethylsulfanyl-pyrimidine-5-carbonitrile

NaH (172 mg, 4.31 mmol, 60%) was added to a solution of EtSH (178 mg,2.87 mmol) in dry THF (5 mL) at 0° C. under N₂. The resulting suspensionwas slowly added to a solution of 2, 4-dichloropyrimidine-5-carbonitrile(2-1, 500 mg, 2.87 mmol) in dry THF (10 mL). The reaction was stirred at−20° C. for 1 h. The reaction mixture was quenched by addition ofaqueous NH₄Cl (20 mL) at 0° C., and then extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford a mixture of2-chloro-4-ethylsulfanyl-pyrimidine-5-carbonitrile and4-chloro-2-ethylsulfanyl-pyrimidine-5-carbonitrile as yellow oil. LCMS:RT 0.793 min, m/z=199.9 [M+H]⁺.

2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfanyl-pyrimidine-5-carbonitrile(47) and4-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-2-ethylsulfanyl-pyrimidine-5-carbonitrile

To a mixture of 2-chloro-4-ethylsulfanyl-pyrimidine-5-carbonitrile and4-chloro-2-ethylsulfanyl-pyrimidine-5-carbonitrile (200 mg, 1 mmol) inn-BuOH (2 mL) was added2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (246 mg, 1.5mmol) and TEA (50 mg, 500.85 μmol) at 25° C. under N₂. The mixture wasthen heated at 120° C. under microwave for 1.5 h. The reaction mixturewas concentrated under reduced pressure. The residue was purified byprep-HPLC (neutral) to give2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfanyl-pyrimidine-5-carbonitrileand4-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-2-ethylsulfanyl-pyrimidine-5-carbonitrile.

2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfanyl-pyrimidine-5-carbonitrile(D-47)

¹H NMR (400 MHz, CDCl₃): δ 8.26-8.39 (m, 1H), 8.09-8.18 (m, 1H),6.75-6.97 (m, 1H), 3.25 (q, J=7.06 Hz, 2H), 2.29 (br. s., 3H), 1.93-2.05(m, 6H), 1.42 (t, J=7.50 Hz, 3H); HPLC: RT 2.597 min: MS: m/z: 328.2[M+H]⁺.

4-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-2-ethylsulfanyl-pyrimidine-5-carbonitrile

¹H NMR (400 MHz, CDCl₃): δ 8.36 (s, 1H), 8.12 (br. s., 1H), 6.70 (br.s., 1H), 3.11 (q, J=7.35 Hz, 2H), 2.28 (s, 3H), 1.97-2.03 (m, 6H), 1.38(t, J=7.28 Hz, 3H); HPLC: RT 2.382 min; MS: m/z: 328.2 [M+H]⁺.

Example D-3 Synthesis of2-[4-[(5-chloro-4-ethylsulfanyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(D-44) 2,5-dichloro-4-ethylsulfanyl-pyrimidine

NaH (654 mg, 16.35 mmol, 60%) was added to a solution of ethanethiol(677 mg, 10.90 mmol) in dry THF (10 mL) at 0° C. under N₂. The resultingsuspension was slowly added to a solution of 2,4,5-trichloropyrimidine(2 g, 10.90 mmol) in dry THF (15 mL) at −20° C. under N₂. The reactionwas then stirred at −20° C. for 1 h. The mixture was poured into aqueousNH₄Cl (50 mL), extracted with EtOAc (3×20 mL). The combined organiclayer was washed with brine, dried over Na₂SO₄, concentrated to afford2,5-dichloro-4-ethylsulfanyl-pyrimidine as yellow solid. LCMS: RT 0.876min, m/z=209.0 [M+H]⁺.

2-[4-[(5-chloro-4-ethylsulfanyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(D-44)

To a mixture of 2,5-dichloro-4-ethylsulfanyl-pyrimidine (200 mg, 956.48μmol) and 2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (235mg, 1.43 mmol) in n-BuOH (3 mL) was added TEA (290 mg, 2.87 mmol) at 25°C. under N₂. The mixture was heated under microwave at 120° C. for 1.5h. The mixture was cooled to 25° C. and concentrated under reducedpressure. The residue was purified by prep-HPLC (neutral) to afford2-[4-[(5-chloro-4-ethylsulfanyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(D-44). ¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 1H), 8.03 (s, 1H), 6.53 (br.s., 1H), 3.20 (q, J=7.50 Hz, 2H), 2.28 (s, 3H), 1.99 (s, 6H), 1.41 (t,J=7.28 Hz, 3H); HPLC: RT 3.47 min: MS: m/z: 337.1 [M+H]⁺.

Example D-4 Synthesis of2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(D-45) 2-chloro-4-ethylsulfanyl-5-(trifluoromethyl)pyrimidine and4-chloro-2-ethylsulfanyl-5-(trifluoromethyl)pyrimidine

NaH (138 mg, 3.45 mmol, 60%) was added to a solution of ethanethiol (143mg, 2.30 mmol, 170.12 μL) in dry THF (5 mL) at 0° C. under N₂. Theresulting suspension was slowly added to a solution of2,4-dichloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.30 mmol) in dryTHF (10 mL) at −20° C. under N₂. The reaction was then stirred at −20°C. for 1 h. The mixture was poured into aqueous NH₄Cl (50 mL), extractedwith EtOAc (3-20 mL). The combined organic layer was washed with brine,dried over Na₂SO₄, concentrated to afford a mixture of2-chloro-4-ethylsulfanyl-5-(trifluoromethyl)pyrimidine and4-chloro-2-ethylsulfanyl-5-(trifluoromethyl)pyrimidine as yellow oil.

2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(D-45) and2-[4-[[2-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

To a mixture of 2-chloro-4-ethylsulfanyl-5-(trifluoromethyl)pyrimidineand 4-chloro-2-ethylsulfanyl-5-(trifluoromethyl)pyrimidine (300 mg, 1.24mmol) in n-BuOH (3 mL) was added2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (305 mg, 1.86mmol) and TEA (375 mg, 3.71 mmol) at 25° C. under N₂. The mixture washeated in microwave at 120° C. for 1.5 h. The reaction mixture wasconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (neutral) to give2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(45) and2-[4-[[2-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile.

2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile(D-45)

¹H NMR (400 MHz, CDCl₃): δ 8.31 (br. s., 1H), 8.12 (s, 1H), 6.73 (br.s., 1H), 3.23 (q, J=7.53 Hz, 2H), 2.29 (s, 3H), 1.95-2.06 (m, 6H), 1.40(t, J=7.28 Hz, 3H); HPLC: RT 3.60 min: MS: m z: 371.2 [M+H]⁺.

2-[4-[[2-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile

¹H NMR (400 MHz, CDCl₃): δ 8.33 (s, 1H), 8.14 (s, 1H), 6.53 (br. s.,1H), 3.10 (q, J=7.20 Hz, 2H), 2.25 (s, 3H), 2.00 (s, 6H), 1.37 (t,J=7.28 Hz, 3H); HPLC: RT 3.30 min; MS: m/z: 371.2 [M+H]⁺.

Example D-5 Synthesis of2-(1-((3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile(D-1)2-(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile

To a mixture of PPh₃ (2.63 g, 10 mmol) in THF (30 mL) was added DIAD (2mL, 10 mmol), 3-methyl-4-nitro-1H-pyrazole (850 mg, 6.7 mmol) and2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (982 mg, 8 mmol) at 25° C.The mixture was stirred at 25° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=50:1 to 5:1) to give2-(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile.

2-(1-((4-amino-3-methyl-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile

To a mixture of2-(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile(400 mg, 1.82 mmol) in EtOH (2 mL) was added Fe (507 mg, 9.08 mmol) andNH₄Cl (486 mg, 9.08 mmol) in one portion at 25° C. under N₂. The mixturewas heated to 90° C. and stirred for 1 h. The mixture was concentratedunder reduced pressure. The residue was purified by prep-TLC (SiO₂,PE:EtOAc=1:1) to give2-(1-((4-amino-3-methyl-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrileas pale yellow oil.

2-(1-((3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile(D-1)

To a mixture of2-(1-((4-amino-3-methyl-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile(100 mg, 0.53 mmol) and2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (110 mg, 0.53mmol) in n-BuOH (2 mL) was added TEA (0.2 mL) in one portion at 25° C.under N₂. The mixture was stirred at 25° C. for 1 h. The reactionmixture was concentrated under reduced pressure to remove n-BuOH. Theresidue was purified by prep-HPLC (neutral) to give2-(1-((3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile(D-1). ¹H NMR (400 MHz, CDCl₃): δ 7.98-8.27 (m, 1H), 7.90 (d, J=20 Hz,1H), 4.11 (s, 2H), 3.09 (d, J=16 Hz, 3H), 2.41-2.61 (m, 2H), 2.10-2.32(m, 3H), 0.89 (br. s., 2H), 0.73 (br. s., 2H); HPLC: RT 1.63 min; MS:m/z: 366.1 [M+H]⁺.

Example D-6, D-7, and D-8 Synthesis ofN2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-2),N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(First eluting stereoisomer, D-3), andN2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Second eluting stereoisomer, D-4)7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoleand7-(5-methyl-4-nitro-1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

To a mixture of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (1 g, 8.06mmol) and 3-methyl-4-nitro-1H-pyrazole (1.13 g, 8.87 mmol) in THF (20mL) was added PPh₃ (3.17 g, 12.09 mmol) and then DIAD (2.44 g, 12.09mmol, 2.4 mL) dropwise at 0° C. over a period of 30 min under N₂. Themixture was warmed to 20° C. and stirred for 12 h, then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (gradient PE:EtOAc from 10:1 to 0:1) to give the mixtureof7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoleand7-(5-methyl-4-nitro-1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoleas a white solid. LCMS: RT 0.112 min, m/z=234.1 [M+H]⁺.

1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amineand1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-amine

To a solution of7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoleand7-(5-methyl-4-nitro-1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole(650 mg, 2.79 mmol) in MeOH (20 mL) was added Pd—C (10%, 0.3 g) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 20° C. for 4 h, thenfiltered and concentrated under reduced pressure, to give the mixture of1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amineand1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-amineas a light yellow solid. LCMS: RT 0.62-0.878 min, m/z=204.2 [M+H]⁺.

N2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-2),N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-3), andN2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-4)

To a solution of the mixture1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amineand1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-amine(220 mg, 1.08 mol) and2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (251.35 mg, 1.19mol, 1.10 eq) in 1,4-dioxane (2 mL) was added TFA (246 mg, 2.16 mol,0.16 mL) at 20° C. The mixture was heated to 90° C. and stirred for 1 h.The mixture was cooled to 20° C. and concentrated under reducedpressure. To the residue was added aq. sat. NaHCO₃, extracted with EtOAc(3×5 mL). The combined organics were washed with brine (5 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by prep-HPLC (neutral) to giveN2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-2) andN2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,which was further purified by chiral SFC to give the correspondingenantiomerN2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(First eluting stereoisomer. D-3) andN2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Second eluting stereoisomer, D-4).

N2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-2)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.09 (s, 1H), 7.76 (br. s., 1H), 7.12 (s,1H), 6.96 (s, 1H), 6.44 (br. s., 1H), 5.55-5.66 (m, 1H), 5.13 (br. s.,1H), 4.39-4.51 (m, 1H), 4.10 (t, J=11.04 Hz, 1H), 3.08-3.26 (m, 2H),3.00 (d, J=4.52 Hz, 3H), 2.40 (s, 3H); HPLC: RT: 1.703 min; MS: m/z:379.1 [M+H]⁺.

N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(First eluting stereoisomer, D-3)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.09 (br. s., 1H), 7.89 (s, 1H), 7.18 (s,1H), 6.99 (s, 1H), 6.72 (br. s., 1H), 5.57-5.68 (m, 1H), 5.19 (br. s.,1H), 4.22 (br. s., 1H), 3.99-4.12 (m, 1H), 3.02-3.24 (m, 2H), 2.97 (d,J=3.09 Hz, 3H), 2.25 (s, 3H); HPLC: RT 1.769 min; MS: m/z: 379.1 [M+H]⁺;SFC: RT 2.71 min.

N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Second eluting stereoisomer, D-4)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.09 (br. s., 1H), 7.88 (br. s., 1H),7.18 (s, 1H), 6.99 (s, 1H), 6.66 (br. s., 1H), 5.58-5.67 (m, 1H), 5.18(br. s., 1H), 4.22 (br. s., 1H), 4.03-4.12 (m, 1H), 3.04-3.24 (m, 2H),2.97 (br. s., 3H) 2.24 (s, 3H); HPLC: RT 1.768 min; MS: m/z: 379.1[M+H]⁺; SFC: RT 3.21 min.

Example D-9 and D-10 Synthesis ofN2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-5) andN2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-6) (1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanoland (1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol

To a solution of [1-(hydroxymethyl)cyclopropyl]methanol (9-1, 3 g, 29.37mmol), 3-methyl-4-nitro-1H-pyrazole (3.39 g, 26.70 mmol) and PPh₃ (7 g,26.70 mmol) in THF (30 mL) was added dropwise DIAD (5.4 g, 26.70 mmol)at 0° C. over 30 min. After addition, the mixture was stirred at thistemperature for 30 min. The resulting mixture was stirred at 25° C. for11 h. The reaction mixture was diluted with H₂O (90 mL) and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,PE:EtOAc=10:1 to 0:1) to give a mixture of(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol and(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol as anoff-white solid, which was used into the next step without furtherpurification. LCMS: RT 0.568 min, m/z=212.2 [M+H]⁺.

(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methylmethanesulfonate and(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methylmethanesulfonate

To a solution of(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol and(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol (5.2g, 24.62 mmol) and Et₃N (7.47 g, 73.86 mmol) in DCM (50 mL) was addeddropwise MsCl (3.38 g, 29.54 mmol) at 0° C. for 0.5 h. The mixture wasstirred at 0° C. for 0.5 h. The reaction mixture was diluted with H₂O(50 mL) and extracted with DCM (3×10 mL). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methylmethanesulfonate and(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methylmethanesulfonate as a yellow oil. The crude product was used into thenext step without further purification. LCMS: RT 1.018 min, m z=290.0[M+H]⁺.

1-((1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,2,4-triazoleand1-((1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,2,4-triazole

To a solution of 1H-1,2,4-triazole (2.01 g, 29.04 mmol) in DMF (30 mL)was added NaH (1.16 g, 29.04 mmol, 60% purity) at 0° C. After addition,the mixture was stirred at this temperature for 0.5 h, and then(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methylmethanesulfonate and(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methylmethanesulfonate (7 g, 24.20 mmol) in DMF (20 mL) was added dropwise at0° C. The resulting mixture was stirred at 50° C. for 3.5 h. Thereaction mixture was quenched by addition H₂O (150 mL) at 0° C., andextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, PE:EtOAc=10:1 to 0:1) to give a mixture of1-((1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,2,4-triazoleand1-((1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,2,4-triazoleas a pale-yellow solid, which was used into the next step withoutfurther purification. LCMS: RT 0.604 min, m/z=263.2 [M+H]⁺.

1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyrazol-4-amineand1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyrazol-4-amine

To a solution of1-((1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,2,4-triazoleand1-((1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,2,4-triazole(1 g, 3.81 mmol) in MeOH (20 mL) was added Pd—C (10%, 0.32 g) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 25° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated to givea mixture of1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyrazol-4-amineand1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyrazol-4-amineas a brown oil, which was used into the next step without furtherpurification.

N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-5) andN2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-6)

A mixture of1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyrazol-4-amineand1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyrazol-4-amine(200 mg, 861.03 μmol),2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (164 mg, 774.93μmol) and Et₃N (261 mg, 2.58 mmol) were taken up into a microwave tubein n-BuOH (5 mL). The sealed tube was heated at 120° C. for 1.5 h undermicrowave. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (neutral) to giveN2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-6) andN2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-5).

N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-5)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.25-8.34 (m, 1H), 8.08-8.20 (m, 1H),7.98-8.04 (m, 1H), 7.96 (m, 1H), 6.49-6.78 (m, 1H), 5.10-5.37 (m, 1H),3.99-4.06 (m, 2H), 3.82-3.92 (m, 2H), 3.04-3.16 (m, 3H), 2.29 (s, 3H),0.85-0.89 (m, 2H), 0.81-0.85 (m, 2H): HPLC: RT 1.973 min; MS: m/z: 408.2[M+H]⁺.

N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-6)

¹H NMR (400 MHz. CDCl₃): δ ppm 8.32 (s, 1H), 8.07-8.14 (m, 1H), 7.97 (s,1H), 7.69-7.90 (m, 1H), 6.38-6.62 (m, 1H), 5.09-5.24 (m, 1H), 4.12 (s,2H), 3.90 (s, 2H), 3.02 (d, J=4.52 Hz, 3H), 2.12 (s, 3H), 0.85-0.91 (m,2H), 0.77-0.83 (m, 2H); HPLC: RT 1.913 min: MS: m/z: 408.2 [M+H]⁺.

Example D-11 and D-12 Synthesis ofN4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-7) andN4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-8) 5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one

To a solution of 5-hydroxypiperidin-2-one (4.5 g, 39.09 mmol) in DMF wasadded imidazole (7.98 g, 117.27 mmol), followed by TBDPSCl (16.11 g,58.64 mmol) at 0° C. The mixture was stirred at 20° C. for 16 h. Thesolution was added with water (120 mL), extracted with EtOAc (3×30 mL).The organic layers were combined, washed with brine (3×20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=10:1to 1:1) to give compound 5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-oneas an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.62-7.69 (m, 4H),7.42-7.48 (m, 2H), 7.36-7.42 (m, 4H), 6.19 (br. s., 1H), 4.06-4.12 (m,1H), 3.15-3.27 (m, 2H), 2.66 (ddd, J=17.42, 9.48, 6.17 Hz, 1H), 2.27(dt, J=17.86, 5.84 Hz, 1H), 1.74-1.95 (m, 2H), 1.02-1.12 (m, 9H).

5-[tert-butyl(diphenyl)silyl]oxypiperidine-2-thione

To a solution of 5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one (3 g,8.49 mmol) in toluene (5 mL) was added lawesson's reagent (1.72 g, 4.25mmol). The mixture was stirred at 110° C. for 2 h. The reaction solutionwas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (PE:EtOAc=10:1 to 3:1) to give5-[tert-butyl(diphenyl)silyl]oxypiperidine-2-thione as a yellow gum.LCMS: RT 0.940 min, m/z=370.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.64(dd, J=6.46, 5.08 Hz, 4H), 7.44-7.50 (m, 2H), 7.38-7.43 (m, 4H), 4.13(q, J=6.86 Hz, 2H), 3.11-3.29 (m, 3H), 2.89 (dt, J=18.95, 5.46 Hz, 1H),1.70-1.90 (m, 2H), 1.07 (s, 9H).

Tert-butyl-[(6-methylsulfanyl-2,3,4,5-tetrahydropyridin-3-yl)oxyl]-diphenyl-silane

To a solution of 5-[tert-butyl(diphenyl)silyl]oxypiperidine-2-thione(2.2 g, 5.95 mmol) in THF (50 mL) was added K₂CO₃ (4.11 g, 29.75 mmol)and Mel (4.22 g, 29.75 mmol). The mixture was stirred at 20° C. for 16h. The reaction mixture was filtered through a pad of celite. The cakewas washed with EtOAc (50 mL), and the filtrate was washed with water(20 mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to giveTert-butyl-[(6-methylsulfanyl-2,3,4,5-tetrahydropyridin-3-yl)oxyl]-diphenyl-silaneas yellow gum, which was used in next step without further purification.¹H NMR (400 MHz, CDCl₃): δ 7.66 (m, 4H), 7.33-7.49 (m, 6H), 3.93 (quin,J=5.02 Hz, 1H), 3.54-3.73 (m, 2H), 2.53-2.64 (m, 1H), 2.27 (s, 3H),2.15-2.24 (m, 1H), 1.74 (q, J=6.40 Hz, 2H), 1.00-1.16 (s, 9H).

Tert-butyl-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)oxyl]-diphenyl-silane

To a solution ofTert-butyl-[(6-methylsulfanyl-2,3,4,5-tetrahydropyridin-3-yl)oxyl]-diphenyl-silane(1.9 g, 4.95 mmol) in EtOH (20 mL) was added acetohydrazide (477 mg,6.44 mmol). The mixture was stirred at 80° C. for 16 h. The reaction wasconcentrated under reduced pressure. The residue was added with water(20 mL), extracted with EtOAc (3×10 mL). The organic layers werecombined, washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give a crude oftert-butyl-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)oxyl]-diphenyl-silaneas a colorless gum, which was used in next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 7.66-7.68 (m, 2H), 7.54-7.56(m, 2H), 7.36-7.47 (m, 6H), 4.36 (d, J=3.26 Hz, 1H), 3.49-3.65 (m, 2H),2.91-3.29 (m, 2H), 2.18-2.24 (m, 3H), 1.75-2.15 (m, 2H), 1.03 (s, 9H).

3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-ol

To a solution ofTert-butyl-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)oxyl]-diphenyl-silane(1.9 g, 4.85 mmol) in MeOH (30 mL) was added KF (4.23 g, 72.75 mmol).The mixture was stirred at 80° C. for 16 h. The reaction mixture wasconcentrated under reduced pressure. The residue was added with DCM:MeOH(50 mL, ratio=10:1), stirred for 10 min, filtered and the filtrate wasconcentrated under reduced pressure. The residue was added with MTBE (15mL), stirred for 10 min, filtered and the solid was dried under reducedpressure to give3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-ol as ayellow solid. ¹H NMR (400 MHz, CDCl₃): δ 4.35 (dd, J=6.17, 2.21 Hz, 1H),3.73-3.96 (m, 2H), 2.78-2.90 (m, 2H), 2.18-2.29 (m, 3H), 1.83-2.07 (m,2H).

(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methanesulfonate

To a solution of3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-ol (400 mg,2.61 mmol) in DCM (50 mL) was added TEA (528 mg, 5.22 mmol) and followedby MsCl (448 mg, 3.92 mmol). The mixture solution was stirred at 0° C.for 2 h. The reaction was added with water (5 mL), extracted with DCM(5×10 mL). The organic layers were combined, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a crude(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methanesulfonate as a yellow oil, which was used in next step withoutfurther purification. ¹H NMR (400 MHz, CDCl3): δ 5.36-5.43 (m, 1H),3.99-4.25 (m, 2H), 3.05-3.18 (m, 5H), 2.36-2.52 (m, 4H), 2.03-2.14 (m,1H).

3-methyl-6-(3-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridineand3-methyl-6-(5-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

To a solution of 3-methyl-4-nitro-1H-pyrazole (1-1, 398 mg, 3.13 mmol)in DMF (10 mL) was added NaH (125 mg, 3.13 mmol, 60% purity) at 0° C.,then the reaction was stirred at 20° C. for 1 h. Then,(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methanesulfonate (604 mg, 2.61 mmol, 70% purity) in DMF (4 mL) was addedto the solution at 20° C. Then, the mixture was stirred at 80° C. for 12h. The reaction solution was added with NH₄Cl solution (20 mL),extracted with DCM:MeOH (20 mL×3, ratio=3:1). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by prep-TLC (DCM:MeOH=5:1) togive a mixture of3-methyl-6-(3-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridineand3-methyl-6-(5-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridineas a yellow gum. LCMS: RT 0.925 min, m/z=263.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.25 (s, 0.6H), 8.13 (s, 0.3H), 4.68-4.81 (m, 1H), 4.14-4.42(m, 2H), 3.02-3.31 (m, 2H), 2.77 (s, 1H), 2.55 (s, 2H), 2.44-2.53 (m,4H), 2.43 (s, 1H).

5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-amineand3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-amine

To a mixture of3-methyl-6-(3-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridineand3-methyl-6-(5-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine(100 mg, 381.29 μmol) in MeOH (10 mL) was added Pd/C (10%, 50 mg) underN₂. The suspension was degassed and purged with H₂ for 3 times. Themixture was stirred under H₂ (15 psi) at 20° C. for 5 h. The reactionsolution was filtered through a pad of celite, the filtrate wasconcentrated under reduced pressure to give a crude5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-amineand3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-amine.LCMS: RT 0.173 min, m/z=233.1 [M+H]⁺.

N4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-7) andN4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-8)

A mixture of5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-amineand3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-amine(70 mg, 301.36 μmol),2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (64 mg, 301.36μmol) and TEA (91 mg, 904.08 μmol) in 1,4-dioxane (10 mL) was degassedand purged with N₂ for 3 times, and then the mixture was stirred at 110°C. for 12 h under N₂. The reaction solution was concentrated underreduced pressure. The crude product was purified by prep-HPLC (HCOOH) togiveN4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-7, HCOOH salt) andN4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-8, HCOOH salt).

N4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-7)

¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 0.39H), 8.07 (s, 1H), 7.90 (s, 1H),5.50 (br. s., 0.14H), 5.28 (br. s., 0.8H), 4.65 (br. s., 1H), 4.39 (dd,J=12.11, 9.22 Hz, 1H), 4.15 (dd, J=12.36, 5.58 Hz, 1H), 3.20-3.31 (m,1H), 2.97-3.09 (m, 4H), 2.39-2.45 (m, 4H), 2.33-2.42 (m, 4H); HPLC: RT2.754 min; MS: m/z: 408.2 [M+H]⁺.

N4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-8)

¹H NMR (400 MHz. CDCl₃): δ 8.22 (s, 0.52H), 8.09 (s, 1H), 7.96 (s, 1H)5.34 (br. s., 1H), 4.71 (s, 1H) 4.18-4.35 (m, 2H) 3.22 (d, J=17.07 Hz,1H), 3.00-3.13 (m, 3H), 2.43 (m, 5H), 2.29 (s, 3H); HPLC: RT 2.847 min;MS: m/z: 408.2 [M+H]⁺.

Example D-13 Synthesis ofN2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-9) 1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine

To a solution of 1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazole(13-1, 100 mg, 452.16 μmol) in MeOH (10 mL) was added Pd—C (10%, 50 mg)under N₂ at 20° C. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred under H₂ (15 psi) at 40°C. for 5 h. The reaction mixture was filtered and the filtrate wasconcentrated, to give1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine was obtained as ayellow oil. LCMS: RT 1.037 min, m/z=192.2 [M+H]⁺.

N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-9)

2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (5-5, 54 mg,253.69 μmol), 1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine (97mg, 507.38 μmol) and TEA (51 mg, 507.38 μmol, 7 μL) were taken up into amicrowave tube in 1,4-dioxane (1.00 mL) at 20° C. The sealed tube washeated at 120° C. for 1.5 h under microwave. The mixture was cooled to20° C. and concentrated. The residue was purified by prep-HPLC (neutral)to give compoundN2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-9). LCMS: RT 0.605 min, m/z=367.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD): δppm 7.97 (br. s., 1H), 7.62 (br. s., 1H), 6.12-6.52 (m, 1H), 4.31-4.36(m, 2H), 4.16-4.22 (m, 2H), 2.91 (br. s., 3H), 2.24 (s, 3H); HPLC: RT2.216 min. MS: m/z: 367.1[M+H]⁺.

Example D-14 Synthesis ofN2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-10) 1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine

To a solution of 1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole(14-1, 100 mg, 452.16 μmol) (100 mg, 452.16 μmol) in MeOH (10 mL) wasadded Pd—C (10%, 50 mg) under N₂. The suspension was degassed undervacuum and purged with H, several times. The mixture was stirred underH₂ (15 psi) at 40° C. for 5 h. The reaction mixture was filtered and thefiltrate was concentrated to give compound1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine as a black brownoil. LCMS: RT 0.802 min, m/z=192.3 [M+H]⁺.

N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-10)

1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine (73 mg, 381.84μmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (40 mg,190.92 μmol) and TEA (38 mg, 381.84 μmol, 52.93 μL) were taken up into amicrowave tube in 1,4-dioxane (1.00 mL) at 20° C. The sealed tube washeated at 120° C. for 1.5 h under microwave. The mixture was cooled to20° C. and concentrated. The residue was purified by prep-HPLC (neutral)to give compoundN2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-10). LCMS: RT 0.671 min, m/z=367.1 [M+H]⁺; ¹H NMR (400 MHz, MeOD): δppm 8.02 (s, 1H), 7.90 (br. s., 1H), 6.14-6.55 (m, 1H), 4.27-4.34 (m,2H), 4.15-4.22 (m, 2H), 2.97 (s, 3H), 2.22 (s, 3H); HPLC: RT 2.277 min;MS: m/z: 367.1 [M+H]⁺.

Example D-15 Synthesis ofN2-[5-chloro-1-[2-(difluoromethoxy)ethyl]pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-11)N2-[5-chloro-1-[2-(difluoromethoxy)ethyl]pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-11)

Compound 5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-amine (80mg, 378.07 μmol), compound2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (80 mg, 378.07μmol) and TEA (115 mg, 1.13 mmol, 157 μL) were taken up into a microwavetube in 1,4-dioxane (10 mL). The sealed tube was heated at 120° C. for90 min under microwave. After cooling to 20° C., the mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (neutral) to giveN2-[5-chloro-1-[2-(difluoromethoxy)ethyl]pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-11). ¹H NMR (400 MHz, CDCl₃): δ 8.14 (br. s., 2H), 6.60-6.79 (m, 1H),5.99-6.40 (m, 1H), 5.22 (br. s., 1H), 4.36-4.41 (m, 2H), 4.23-4.29 (m,2H), 3.07 (d, J=4.64 Hz, 3H): HPLC: RT 2.521 min; MS: m/z=387.0 [M+H]⁺.

Example D-16 Synthesis ofN2-[5-chloro-1-[[1-(methoxymethyl)cyclopropyl]methyl]pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-12)N2-[5-chloro-1-[[1-(methoxymethyl)cyclopropyl]methyl]pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-12)

To a mixture of compound5-chloro-1-((1-(methoxymethyl)cyclopropyl)methyl)-1H-pyrazol-4-amine (70mg, 324.55 μmol) and compound2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (68.67 mg, 324.55μmol) in 1,4-dioxane (10 mL) was added TFA (74 mg, 649.10 μmol, 48 μL)at 20° C. under N₂. The mixture was heated to 90° C. and stirred for 5h. The mixture was cooled to 20° C. and was adjusted to pH=8 by addingaq. sat. NaHCO₃ and extracted with EtOAc (3-8 mL). The combined organicphase was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (neutral) to giveN2-[5-chloro-1-[[1-(methoxymethyl)cyclopropyl]methyl]pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-12). ¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2H), 6.79 (br. s., 1H),5.18-5.26 (m, 1H), 4.16 (s, 2H), 3.34 (s, 3H), 3.16 (s, 2H), 3.07 (d,J=4.64 Hz, 3H), 0.74-0.78 (m, 2H), 0.55-0.60 (m, 2H); HPLC: RT 2.574min; MS: m/z=391.1 [M+H]⁺.

Example D-17 and D-18 Synthesis of2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]acetamide(D-14) and2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]acetonitrile(D-13) Ethyl 2,2-difluoro-2-(3-methyl-4-nitro-pyrazol-1-yl)acetate

To a solution of 5-methyl-4-nitro-1H-pyrazole (20 g, 157.36 mmol) in DMF(300 mL) was added NaH (9.44 g, 236.04 mmol, 60% purity) at 0° C. underN₂. After addition, the mixture was allowed to 25° C. and stirred for 2h, 1-bromo-3-ethoxy-1,1-difluoro-propan-2-one (51.22 g, 236.04 mmol) wasthen added at 0° C. The mixture was stirred at 25° C. for 16 h. Themixture was poured into aqueous NH₄Cl (900 mL). The aqueous phase wasextracted with MTBE (3×300 mL). The combined organic phase was washedwith brine (2×200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=20:1) to give ethyl2,2-difluoro-2-(3-methyl-4-nitro-pyrazol-1-yl)acetate as a light yellowliquid. LCMS: RT 1.190 min, m/z=250.1 [M+H]⁺.

Ethyl 2-(4-amino-3-methyl-pyrazol-1-yl)-2,2-difluoro-acetate

To a solution of ethyl2,2-difluoro-2-(3-methyl-4-nitro-pyrazol-1-yl)acetate (10 g, 40.13 mmol)in EtOH (100 mL) was added Pd/C (1 g, 10% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ for three times.The mixture was stirred under H₂ (15 psi) at 15° C. for 3 h. Thereaction solution was filtered and the filtrate was concentrated underreduced pressure to give ethyl2-(4-amino-3-methyl-pyrazol-1-yl)-2,2-difluoro-acetate as a brown oil.LCMS: RT 0.23 min, m/z=220 [M+H]⁺

Ethyl2-[4-[bis(tert-butoxycarbonyl)amino]-3-methyl-pyrazol-1-yl]-2,2-difluoro-acetate

A mixture of ethyl2-(4-amino-3-methyl-pyrazol-1-yl)-2,2-difluoro-acetate (8.3 g, 37.87mmol), Boc₂O (12.4 g, 56.81 mmol, 13.05 mL), TEA (6.9 g, 68.17 mmol,9.45 mL) and DMAP (4.63 g, 37.87 mmol) in DCM (160 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 25° C.for 12 h under N₂. The reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=5/1 to 3:1) to give ethyl2-[4-[bis(tert-butoxycarbonyl)amino]-3-methyl-pyrazol-1-yl]-2,2-difluoro-acetateas a yellow oil. LCMS: RT 0.23 min, m/z=320 [M+H]⁺.

Tert-butylN-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]carbamate

To a solution of ethyl2-[4-(tert-butoxycarbonylamino)-3-methyl-pyrazol-1-yl]-2,2-difluoro-acetate(4 g, 12.53 mmol) in MeOH (10 mL) was added a methanolic solution of NH₃(70 mL). The mixture was stirred at 50° C. for 12 h in an autoclave. Thereaction solution was concentrated under reduced pressure to givetert-butylN-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]carbamateas a yellow solid. LCMS: RT 0.705 min, m/z=291.2 [M+H]⁺. ¹H NMR (400MHz, chloroform-d): δ 8.01-8.21 (m, 1H), 6.83 (s, 1H), 6.01-6.31 (br,2H), 3.49 (s, 1H), 2.23 (s, 3H), 1.50-1.55 (m, 9H),2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]acetamide(D-14)

To a solution of tert-butylN-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]carbamate(500 mg, 1.72 mmol) and2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (400 mg, 1.89mmol) in 1,4-dioxane (30 mL) was added p-TsOH (296 mg, 1.72 mmol). Themixture was stirred at 100° C. for 10 h. The reaction solution wasconcentrated under reduced pressure. The residue was adjusted to pH 7with aq. NaHCO₃, extracted with EtOAc (3×10 ml). The organic layers werecombined, washed with brine (5 ml), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was washed withMeCN (5 mL), the solid was filtered and dried under reduced pressure togive2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]acetamide(14). Additional crude compound 14 was obtained by concentration of theMeCN mother liquor. ¹H NMR (400 MHz, chloroform-d): δ 9.33 (br. s., 1H),8.58 (s, 1H), 8.34 (br. s., 2H), 8.17 (s, 1H), 7.16 (br. s., 1H), 2.90(d, J=4.27 Hz, 3H), 2.24 (s, 3H); HPLC: RT 2.49 min; MS: m/z: 366.0[M+H]⁺.

2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]acetonitrile(D-13)

The solution of2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]acetamide(100 mg, 273.78 μmol) in POCl₃ (3.3 g, 21.52 mmol, 2.00 mL) was heatedat 90° C. for 10 h. The reaction solution was concentrated under reducedpressure. The residue was adjusted to pH 7 with aq. NaHCO₃, extractedwith EtOAc (3×10 mL), organic layers were combined, washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by prep-TLC (PE:EtOAc=1:1) andfurther purified by prep-HPLC (FA) to give2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]acetonitrile(D-13). ¹H NMR (400 MHz, chloroform-c): δ 8.42 (s, 1H), 8.19 (s., 1H),6.71 (br. s., 1H), 5.30 (br. s., 1H), 3.10 (d, J=4.27 Hz, 3H), 2.37 (s,3H); HPLC: RT 2.48 min; MS: m/z: 348.2 [M+H]⁺

Example D-19 and D-20 Synthesis ofN2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-15) andN2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-16) 2-(5-methyl-4-nitro-pyrazol-1-yl)ethanol and2-(3-methyl-4-nitro-pyrazol-1-yl)ethanol

A mixture of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34 mmol),2-bromoethanol (9.83 g, 78.68 mmol, 5.59 mL) and K₂CO₃ (16.31 g, 118.02mmol) in CH₃CN (50 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 80° C. for 16 h under N₂. The mixturewas cooled to 20° C. and concentrated under reduced pressure. Theresidue was poured into ice water (100 mL). The aqueous phase wasextracted with EtOAc (3×35 mL). The combined organic phase was washedwith brine (35 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=2:1), to give2-(5-methyl-4-nitro-pyrazol-1-yl)ethanol and2-(3-methyl-4-nitro-pyrazol-1-yl)ethanol as a yellow oil. LCMS: RT 0.161min, m/z=172.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.20 (s, 1H), 8.03 (s,1H), 4.14-4.22 (m, 4H), 3.94-4.03 (m, 4H), 3.07 (d, J=5.27 Hz, 2H), 2.64(s, 3H), 2.47 (s, 3H).

1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazole and1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole

To a solution of 2-(5-methyl-4-nitro-pyrazol-1-yl)ethanol (19-2, 4.26 g,24.89 mmol), 2-(3-methyl-4-nitro-pyrazol-1-yl)ethanol and CuI (948 mg,4.98 mmol) in CH₃CN (100 mL) was added a solution of2,2-difluoro-2-fluorosulfonyl-acetic acid (6.65 g, 37.34 mmol, 3.87 mL)in CH₃CN (10 mL) dropwise at 55° C. over a period of 30 min under N₂.The reaction mixture was stirred at 55° C. for another 2 h. The mixturewas cooled to 20° C. and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=5:1),to give a mixture of1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazole and1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole as a yellow oil.LCMS: RT 0.707 min, m/z=222.1 [M+H]⁺.

1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine and1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine

To a mixture of 1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazoleand 1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole (800 mg, 1.81mmol) and NH₄Cl (484 mg, 9.05 mmol) in EtOH (20 mL) and H₂O (5 mL) wasadded Fe (505 mg, 9.05 mmol). The mixture was stirred at 80° C. for 2 h.The mixture was cooled to 20° C. and concentrated in reduced pressure.The residue was poured into ice water (10 mL). The aqueous phase wasextracted with EtOAc (5×5 mL). The combined organic phase was washedwith brine (5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure, to give the crude product1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine and1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine, which was used inthe next step without further purification. LCMS: RT 0.095 min,m/z=192.2 [M+H]⁺.

N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-15) andN2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-16)

To a mixture of 1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amineand 1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine (100 mg,523.07 μmol), and 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine(130 mg, 575.38 μmol) in 1,4-dioxane (5.00 mL) was added TEA (159 mg,1.57 mmol) under N₂. The mixture was stirred at 120° C. for 2 h. Themixture was cooled to 20° C. and concentrated under reduced pressure.The residue was purified by prep-HPLC (FA condition), to giveN2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-15) andN2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-16, peak 2).

N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-15)

¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.75 (br. s., 1H), 5.91-6.36(m, 1H), 5.06 (br. s., 1H), 4.27-4.32 (m, 2H), 4.22-4.27 (m, 2H),3.44-3.53 (m, 2H), 2.24 (s, 3H), 1.66 (br. s., 1H), 1.20-1.27 (m, 3H);HPLC: RT 1.75 min; MS: m/z=381.1 [M+H]⁺.

N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-16)

¹H NMR (400 MHz, CDCl₃): δ 8.12 (br. s., 1H), 7.87 (s, 1H), 5.94-6.39(m, 1H), 5.13 (br. s., 1H), 4.26-4.33 (m, 2H), 4.17-4.24 (m, 2H),3.48-3.59 (m, 2H), 2.26 (s, 3H), 1.90 (br. s., 1H), 1.28 (t, J=7.28 Hz,3H); HPLC: RT 2.508 min; MS: m/z=381.1 [M+H]⁺.

Example D-21 and D-22 Synthesis ofN2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-19) andN2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-20) (R)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol and(R)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol

To a mixture of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34 mmol) and(R)-2-methyloxirane (3.43 g, 59.01 mmol, 4.13 mL) in DMF (50 mL) wasadded Cs₂CO₃ (19.23 g, 59.01 mmol) at 20° C. The mixture was heated to80° C. and stirred for 15 h then cooled to 20° C. and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1 to 0:1) to give the mixture of(R)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol and(R)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow liquid.LCMS: RT 0.133 min, m/z=186.1 [M+H]⁺.

(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-4-nitro-1H-pyrazole and(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-4-nitro-1H-pyrazole

To a solution of the mixture(R)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol and(R)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (3 g, 16.2 mmol) inCH₃CN (150 mL) was added CuI (617 mg, 3.24 mmol), then a solution of2,2-difluoro-2-fluorosulfonyl-acetic acid (4.33 g, 24.30 mmol, 2.5 mL)in CH₃CN (150 mL) dropwise at 20° C. over a period of 30 min under N₂.The reaction mixture was warmed to 55° C. and stirred for 2 h thencooled to 20° C. and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (PE:EtOAc=10:1 to 0:1)to give the mixture of(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-4-nitro-1H-pyrazole and(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-4-nitro-1H-pyrazole as ayellow oil. LCMS: RT 0.873 min, m/z=236.1 [M+H]⁺.

(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-1H-pyrazol-4-amine and(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-1H-pyrazol-4-amine

To a solution of the mixture(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-4-nitro-1H-pyrazole and(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-4-nitro-1H-pyrazole (4 g,17.01 mmol) in EtOH (96 mL) and H₂O (24 mL) was added NH₄Cl (4.55 g,85.04 mmol, 2.97 mL) and Fe (4.75 g, 85.04 mmol) at 20° C. The mixturewas heated to 80° C. and stirred for 2 h then cooled to 20° C. andconcentrated under reduced pressure. The residue was washed withDCM:MeOH=10:1 (3×10 mL) then filtered and the filtrate was concentratedunder reduced pressure to give the mixture compound(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-1H-pyrazol-4-amine and(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-1H-pyrazol-4-amine as a lightyellow oil. LCMS: RT 1.046 min, m/z=206.2 [M+H]⁺.

N2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-19) andN2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-20)

To a solution of the mixture(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-1H-pyrazol-4-amine and(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-1H-pyrazol-4-amine (300 mg,1.46 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine(238 mg, 1.12 mmol) in 1,4-dioxane (3 mL) was added p-TsOH (97 mg,562.30 μmol) at 20° C. The mixture was heated to 90° C. and stirred for2 h, then cooled to 20° C. and adjusted to pH 7-8 by aq. NaHCO₃. Themixture was extracted with EtOAc (3×5 mL), washed with brine (5 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (FA) to give compoundN2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-19) andN2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-20).

N2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-19)

¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (br. s., 1H), 7.76 (br. s., 1H), 6.85(br. s., 1H), 5.80-6.24 (m, 1H), 5.15 (br. s., 1H), 4.59-4.75 (m, 1H),4.04-4.24 (m, 2H), 2.99 (d, J=4.02 Hz, 3H), 2.24 (s, 3H), 1.34 (d,J=6.53 Hz, 3H); HPLC: RT 2.406 min; MS: (M+H⁺) m/z: 381.1; SFC: RT 3.15min.

N2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-20)

¹H NMR (400 MHz, CDCl₃) δ ppm 8.13 (br. s., 1H), 7.89 (br. s., 1H), 6.58(br. s., 1H), 5.85-6.31 (m, 1H), 5.19 (br. s., 1H), 4.55-4.69 (m, 1H),4.13 (d, J=5.52 Hz, 2H), 3.06 (d, J=4.52 Hz, 3H), 2.26 (s, 3H), 1.30 (d,J=6.53 Hz, 3H); HPLC: RT: 2.463 min; MS: (M+H⁺) m/z: 381.1; SFC: RT:3.44 min.

Example D-23 and D-24 Synthesis ofN2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-48) andN2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-21) Ethyl 2-(5-methyl-4-nitro-pyrazol-1-yl)propanoate and ethyl2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate

To a solution of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34 mmol) in DMF(50 mL) was added NaH (1.89 g, 47.21 mmol, 60% purity) at 0° C. underN₂. The mixture was stirred at 20° C. for 1 h, then added with ethyl2-chloropropanoate (10.75 g, 78.68 mmol, 10.05 mL) and stirred for 15 h.The mixture was poured into ice water (250 mL). The aqueous phase wasextracted with EtOAc (3×100 mL). The combined organic phase was washedwith brine (3-100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=2:1), to give a mixture of ethyl2-(5-methyl-4-nitro-pyrazol-1-yl)propanoate and ethyl2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate as a yellow oil. LCMS: RT0.745 min, m/z=228.2 [M+H]⁺.

2-(5-methyl-4-nitro-pyrazol-1-yl)propan-1-ol and2-(3-methyl-4-nitro-pyrazol-1-yl)propan-1-ol

To a mixture of ethyl 2-(5-methyl-4-nitro-pyrazol-1-yl)propanoate andethyl 2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (9.3 g, 40.93 mmol) inMeOH (90 mL) was added NaBH₄ (3.87 g, 102.33 mmol) at 0° C. under N₂.The mixture was stirred at 0° C. for 2 h. The mixture was concentratedunder reduced pressure and purified by silica gel column chromatography(PE:EtOAc=3:1), to give a mixture of2-(5-methyl-4-nitro-pyrazol-1-yl)propan-1-ol and2-(3-methyl-4-nitro-pyrazol-1-yl)propan-1-ol was obtained as a yellowsolid. LCMS: RT 0.707 min, m/z=222.1 [M+H]⁺.

1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-4-nitro-pyrazole and1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole

To a solution of 2-(5-methyl-4-nitro-pyrazol-1-yl)propan-1-ol,2-(3-methyl-4-nitro-pyrazol-1-yl)propan-1-ol (2.08 g, 11.23 mmol) andCuI (428 mg, 2.25 mmol) in CH:CN (20 mL) was added a solution of2,2-difluoro-2-fluorosulfonyl-acetic acid (3 g, 16.85 mmol, 1.74 mL) inCH₃CN (10 mL) dropwise at 55° C. over a period of 30 min under N₂. Thereaction mixture was stirred at 55° C. for 2.5 h. The mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography (PE:EtOAc=6:1), to give a mixture of1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-4-nitro-pyrazole and1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole wasobtained as a yellow oil. LCMS: RT 0.758 min, m/z=236.52 [M+H]⁺.

1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-amine and1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-amine

To a mixture of1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-4-nitro-pyrazole and1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole (760mg, 3.23 mmol) in EtOH (20 mL) was added Fe (902.38 mg, 16.15 mmol) andNH₄Cl (864 mg, 16.15 mmol, 564.87 μL). The mixture was stirred at 80° C.for 2 h. The mixture was cooled to 20° C. and concentrated under reducedpressure. The residue was poured into ice water (10 mL). The aqueousphase was extracted with EtOAc (3×10 mL). The combined organic phase waswashed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure, to give a crude1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-amine and1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-amine, whichwas used into the next step without further purification. LCMS: RT 1.026min, m/z=186.1 [M+H]⁺

N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-48) andN2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-21)

To a mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine(372 mg, 1.75 mmol),1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-amine and1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-amine (300 mg,1.46 mmol) in 1,4-dioxane (10 mL) was added TEA (295 mg, 2.92 mmol,404.75 μL) in one portion under N₂. The mixture was stirred at 120° C.for 2 h. The mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (FA).

N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-48)

¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.85 (br. s., 1H), 6.62 (br.s., 1H), 5.86-6.31 (m, 1H), 5.14 (br. s., 1H), 4.44-4.55 (m, 1H), 4.22(t, J=9.48 Hz, 1H), 4.08 (dd, J=10.36, 5.07 Hz, 1H), 3.00 (d, J=4.85 Hz,3H), 2.18-2.30 (m, 3H), 1.53 (d, J=7.06 Hz, 3H); HPLC: RT 1.94 min; MS:m/z=381.1 [M+H]⁺

N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-21)

¹H NMR (400 MHz, CDCl₃): δ 8.12 (br. s., 1H), 7.92 (br. s., 1H), 6.97(br. s., 1H), 5.88-6.38 (m, 1H), 5.21 (br. s., 1H), 4.47 (d, J=5.52 Hz,1H), 3.99-4.20 (m, 2H), 3.06 (d, J=2.89 Hz, 3H), 2.26 (s, 3H), 1.56 (d,J=6.78 Hz, 3H). HPLC: RT 1.93 min; MS: m/z: 381.1 [M+H]⁺.

Example D-25, D-26, and D-27 Synthesis ofN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(First eluting stereoisomer, D-23),N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Second eluting stereoisomer, D-24), andN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-22)N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(First eluting stereoisomer, D-23),N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Second eluting stereoisomer, D-24), andN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-22)

To a solution of1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-amine(200 mg, 984.06 μmol) and1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amineand 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (222 mg,984.06 μmol) in 1,4-dioxane (5 mL) was added TFA (56 mg, 492.03 μmol).The mixture was stirred at 100° C. for 1 h. The reaction mixture wasdiluted with H₂O (20 mL), and adjusted with aq. NaHCO₃ (10 mL) to pH 8and extracted with EtOAc (3×10 mL). The combined organic layers werewashed with brine (5 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by prep-HPLC (TFA) togive crudeN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Peak 1 in HPLC) and racemicN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Peak 2 in HPLC).

CrudeN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diaminewas further purified by prep-HPLC (FA) to giveN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-22, FA salt, racemers). RacemicN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diaminewas separated by SFC to giveN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-23, First eluting stereoisomer in SFC), andN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-24, Second eluting stereoisomer in SFC).

N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(First eluting stereoisomer, D-23)

¹H NMR (400 MHz, CD₃OD): δ ppm 7.99-8.07 (m, 1H), 7.77-7.87 (m, 1H),7.20-7.27 (m, 1H), 7.08-7.17 (m, 1H), 5.70-5.79 (m, 1H), 4.26-4.36 (m,1H), 4.08-4.22 (m, 1H), 3.38-3.52 (m, 2H), 3.18-3.30 (m, 1H), 2.74-2.90(m, 1H), 2.22 (s, 3H), 1.07-1.24 (m, 3H); HPLC: RT 2.018 min; MS: m/z:393.2 [M+H]⁺; SFC: RT 2.47 min.

N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(Second eluting stereoisomer, D-24)

¹H NMR (400 MHz, CD₃OD): δ ppm 7.99-8.08 (m, 1H), 7.77-7.87 (m, 1H),7.19-7.26 (m, 1H), 7.09-7.16 (m, 1H), 5.70-5.78 (m, 1H), 4.26-4.38 (m,1H), 4.09-4.20 (m, 1H), 3.38-3.51 (m, 2H), 3.19-3.29 (m, 1H), 2.72-2.88(m, 1H), 2.22 (s, 3H), 1.05-1.25 (m, 3H); HPLC: RT 2.016 min; MS: m/z:393.2 [M+H]⁺; SFC: RT 2.67 min.

N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-22)

¹H NMR (400 MHz, CD₃OD): δ ppm 8.11-8.24 (m, 1H), 7.95-8.07 (m, 1H),7.49-7.75 (m, 1H), 7.25 (br. s., 1H), 7.09-7.21 (m, 1H), 5.88-6.01 (m,1H), 4.35-4.51 (m, 1H), 4.12-4.29 (m, 1H), 3.41-3.57 (m, 2H), 3.22-3.31(m, 1H), 2.84-3.04 (m, 1H), 2.34 (s, 3H), 1.18 (m, 3H); HPLC: RT 1.967min: MS: m/z: 393.2 [M+H]⁺.

Example D-28 and D-29 Synthesis oftrans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-25) andtrans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-26) cis-3-benzyloxycyclobutanol

To a solution of 3-benzyloxycyclobutanone (28-1, 19.7 g, 111.8 mmol) inMeOH (200 mL) was added NaBH₄ (6.77 g, 178.9 mmol) at 0° C., and themixture was stirred at 15° C. for 2 h. The reaction mixture was pouredinto water (100 mL) slowly. The methanol was removed under reducedpressure. The residue was extracted with EtOAc (3×50 mL). The organicphase was washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated to give cis-3-benzyloxycyclobutanol as colorless oil. ¹HNMR (400 MHz, CDCl₃): δ ppm 7.29-7.35 (m, 5H), 4.43 (s, 2H), 3.90-3.95(m, 1H), 3.62-3.66 (m, 1H), 2.71-2.75 (m, 2H), 1.83-1.96 (m, 3H).

trans-1-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole andtrans-1-(3-benzyloxycyclobutyl)-3-methyl-4-nitro-pyrazole

To a solution of cis-3-benzyloxycyclobutanol (17 g, 95.4 mmol) and3-methyl-4-nitro-1H-pyrazole (12.1 g, 95.4 mmol) in THF (350 mL) wasadded PPh₃ (37.5 g, 143 mmol). Then, DIAD (28.9 g, 143 mmol) was addedslowly at 0° C., and the mixture was stirred at 15° C. for 20 h. Themixture was quenched with H₂O (100 mL), then filtered. The filtrate wasthen extracted with EtOAc (3×70 mL). The organic phase was washed withbrine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography(PE:EtOAc=10:1 to 7:1), to givetrans-1-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole andtrans-1-(3-benzyloxycyclobutyl)-3-methyl-4-nitro-pyrazole.

trans-3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol andtrans-3-[3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol

To a solution oftrans-1-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole andtrans-1-(3-benzyloxycyclobutyl)-3-methyl-4-nitro-pyrazole (19.5 g, 67.9mmol) in DCM (200 mL) was added BCl₃ (1 M, 26.5 mL) at 0° C., and themixture was stirred at 0° C. for 2 h. The mixture was poured into water(200 mL) slowly, then extracted with DCM (2×100 mL). The organic phasewas washed with aqueous NaHCO₃ (50 mL), brine (40 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel column chromatography (PE/EtOAc=2:1 to 1:1), to givetrans-3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol andtrans-3-[3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol as a mixture as awhite solid.

trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-4-nitro-pyrazole andtrans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-4-nitro-pyrazole

To a mixture of trans-3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol andtrans-3-[3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol (1.4 g, 7.1 mmol) inCH₃CN (100 mL) was added CuI (541 mg, 2.84 mmol) and2,2-difluoro-2-fluorosulfonyl-acetic acid (1.9 g, 10.65 mmol) at 15° C.,and the mixture was stirred at 55° C. for 2 h. The mixture was quenchedwith water (5 mL). The solvent was filtered through celite and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EtOAc=10:1), to givetrans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-4-nitro-pyrazole andtrans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-4-nitro-pyrazole as ayellow solid.

trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-amine andtrans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-amine

To a mixture oftrans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-4-nitro-pyrazole andtrans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-4-nitro-pyrazole (350mg, 1.42 mmol) and NH₄Cl (379 mg, 7.08 mmol) in EtOH (8.8 mL) and H₂O(2.2 mL) was added powder Fe (395 mg, 7.08 mmol) at 15° C., then themixture was stirred at 80° C. for 2 h. The mixture was filtered throughcelite, and the filtrate was concentrated under reduced pressure. Themixture was extracted with EtOAc (2×30 mL). The organic phase was washedwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to givetrans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-amine andtrans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-amine as abrown oil. LCMS: RT 2.06 min, m/z=393.1 [M+H]⁺.

trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-25) andtrans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-26)

To a mixture oftrans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-amine andtrans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-amine (270mg, 1.24 mmol) in 1,4-dioxane (10 mL) was added2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (262 mg, 1.24mmol) and TsOH-H₂O (236 mg, 1.24 mmol) at 15° C. The mixture was warmedto 90° C. and stirred for 2 h. The reaction was quenched with H₂O (1mL), then concentrated under reduced pressure. The crude was purified byprep-HPLC (FA) to givetrans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(25) andtrans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(26).

trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-25)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.08 (s, 1H) 7.71-7.98 (br. s., 1H), 6.23(t, J=3.2 Hz, 1H), 5.20 (t, J=3.2 Hz, 1H), 4.1 (t, J=3.2 Hz, 1H), 4.75(br. s., 1H), 3.03 (s, 3H), 2.97-3.03 (m, 2H), 2.68-2.73 (m, 2H), 2.20(s, 3H): HPLC: RT 2.06 min; MS: m/z: 393.1 [M+H]⁺.

trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-26)

¹H NMR (400 MHz, CDCl₃): δ ppm 8.21 (s, 1H), 8.07 (br. s., 1H), 7.89 (s,1H), 6.22 (t, J=3.2 Hz, 1H), 5.34 (br. s., 1H), 4.96-5.02 (m, 1H),4.81-4.90 (m, 1H) 3.04-3.15 (m, 3H), 2.84-2.96 (m, 2H), 2.65-2.78 (m,2H), 2.31 (s, 3H); HPLC: RT 2.06 min; NIS: m/z: 393.1 [M+H]⁺.

Example D-30 and D-31 Synthesis ofcis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-49) and cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-27)cis-[3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl]cyclobutyl] methanesulfonateand cis-[3-[(1S)-3-methyl-4-nitro-pyrazol-1-yl]cyclobutyl]methanesulfonate

To a mixture of 3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol and3-[(1R)-3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol (2 g, 10.14 mmol) inDCM (20 mL) was added TEA (2.05 g, 20.29 mmol) and MsCl (1.74 g, 15.21mmol) at 0° C., then stirred at 20° C. for 30 min. The reaction mixturewas quenched by water (100 mL) at 0° C., and extracted with DCM (2×50mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe crude product, which was used to the next step directly withoutpurification. The mixture of[3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl]cyclobutyl] methanesulfonate and[3-[(1S)-3-methyl-4-nitro-pyrazol-1-yl] cyclobutyl]methanesulfonate wasobtained as a yellow solid. LCMS: RT 0.715 min, m/z=276.2 [M+H]⁺.

cis-5-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole andcis-3-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole

To a mixture of 1H-pyrazole (30-3, 297 mg, 4.36 mmol) in DMF (10 mL) wasadded NaH (174 mg, 4.36 mmol, 60% purity) at 0° C. and stirred for 30min, then added the mixture of [3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl]cyclobutyl] methanesulfonate and[3-[(1S)-3-methyl-4-nitro-pyrazol-1-yl]cyclobutyl] methanesulfonate (1g, 3.63 mmol) in DMF (1 mL), then heated to 60° C. and stirred for 16 h.Then, a mixture of 1H-pyrazole (297 mg, 4.36 mmol) and NaH (174 mg, 4.36mmol) in DMF (3 mL) was added into the reaction at 0° C., then heated to60° C. and stirred for 16 h. The reaction mixture was quenched by aq.sat. NH₄Cl (100 mL) at 0° C., and extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by silica gel column chromatography(EtOAc/PE=0-50%). The mixture ofcis-5-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole andcis-3-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole was obtainedas a yellow solid. LCMS: RT 0.730 min, m/z=248.2 [M+H]⁺.

cis-5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine andcis-3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine

To a mixture of 5-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazoleand (1S)-3-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole (400 mg,1.62 mmol) in EtOH (8 mL) and H₂O (2 mL) was added Fe (271 mg, 4.86mmol) and NH₄Cl (260 mg, 4.86 mmol) at 0° C. The mixture was heated to90° C. for 1 h. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to give a residue. The residue wasdissolved in acetonitrile (10 mL), and then filtered. The filtrate wasconcentrated under reduced pressure to give crude mixture ofcis-5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine andcis-3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine as a brown oil,which was used to the next step without purification. LCMS: RT 1.126min, m/z=218.2 [M+H]⁺.

cis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-49) and cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-27)

To a mixture of cis-5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amineand cis-3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine (180 mg,828 μmol) in 1,4-dioxane (5 mL) was added TsOH.H₂O (48 mg, 249 μmol) and2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (175 mg, 828μmol) at 20° C. The mixture was heated to 80° C. and stirred for 2 h.The mixture was added with water (1 mL) and stirred for 2 min, thenconcentrated under reduced pressure to give a residue, which waspurified by prep-HPLC (FA condition) to givecis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-49) and cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-27).

cis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-49)

¹H NMR (400 MHz, chloroform-d) δ ppm 2.24 (s, 3H) 2.96-3.18 (m, 5H)3.22-3.36 (m, 2H) 4.50-4.61 (m, 1H) 4.68-4.80 (m, 1H) 5.18 (br. s., 1H)6.31 (d, J=2.20 Hz, 1H) 6.84 (br. s., 1H) 7.54 (s, 1H) 7.67 (br. s., 1H)7.90 (br. s., 1H) 8.09 (br. s., 1H); HPLC: RT 1.72 min; MS: m/z: 393.1[M+H]⁺.

cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-27)

¹H NMR (400 MHz, chloroform-d) δ ppm 2.28 (s, 3H) 3.13 (t, J=8.16 Hz,7H) 4.53-4.75 (m, 2H) 5.25 (br. s., 1H) 6.29 (s, 1H) 6.99 (d, J=13.23Hz, 1H) 7.55 (br. s., 2H) 8.13 (br. s., 1H) 8.21 (br. s., 1H); HPLC: RT1.91 min: MS: m/z: 393.1 [M+H]⁺.

Example D-32 and D-33 Synthesis ofcis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-50) and cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-28) cis-5-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole andcis-3-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole

To a mixture of cis-[3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutyl]methanesulfonate andcis-[3-[-3-methyl-4-nitro-pyrazol-1-yl]cyclobutyl]methanesulfonate (1 g,3.63 mmol) in NMP (10 mL) was added NaSMe (1.02 g, 14.52 mmol) at 20° C.The mixture was heated to 100° C. and stirred for 16 h. The reactionmixture was quenched by aq. sat. NH₄Cl (100 mL) at 0° C., and extractedwith EtOAc (3×50 mL). The combined organic phases were washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by silica gelcolumn chromatography (PE:EtOAc=30:1 to 10:1), to give a mixture ofcis-5-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole andcis-3-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole as a yellowoil. LCMS: RT 0.798 min, m/z=228.2 [M+H]⁺.

cis-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine andcis-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine

To a mixture ofcis-5-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole andcis-3-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole (200 mg,879.97 μmol) in EtOH (4 mL) and H₂O (1 mL) was added Fe (148 mg, 2.64mmol) and NH₄Cl (141 mg, 2.64 mmol) at 0° C. The mixture was heated to90° C. for 1 h. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to give a residue. Then, the residuewas dissolved by MeCN (5 mL) and filtered. The filtrate was concentratedunder reduce pressure to give crudecis-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine andcis-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine as brown oil,which was used in the next step without purification. LCMS: RT 1.113min, m/z=198.1 [M+H]⁺.

cis-N4-methyl-N2-[(5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamineandcis-N4-methyl-N2-[3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a mixture ofcis-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine andcis-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine (190 mg, 963μmol) in 1,4-dioxane (4 mL) was added2-chloro-N-methyl-5-(trifluormethyl)pyrimidin-4-amine (204 mg, 963 μmol)and TsOH-H₂O (55 mg, 289 μmol) at 20° C. The mixture was heated to 80°C. and stirred for 2 h. The mixture was added with water (1 mL) andstirred for 3 min, then concentrated under reduced pressure to give aresidue, which was purified by silica gel column chromatography(DCM:MeOH=20:1 to 5:1), to give a mixture ofcis-N4-methyl-N2-[-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine andcis-N4-methyl-N2-[3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamineas a yellow oil. LCMS: RT 2.747 min, m/z=373.1 [M+H]⁺.

cis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-50) nd cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-28)

To a mixture of N4-methyl-N2-[(1R)-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine andN4-methyl-N2-[(1S)-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(280 mg, 752 μmol) in THF (5 mL) and H₂O (1 mL) was added oxone (229 mg,1.5 mmol) at 0° C. The mixture was stirred at 20° C. for 2 h. Themixture was quenched by aq. Na₂S₂O₃ (60 mL) and extracted with EtOAc(3×20 mL). The organic phase was washed by brine (20 mL), dried overNa₂SO₄, and concentrated under reduced pressure to give a residue, whichwas purified by prep-HPLC (FA condition) to givecis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-50) and cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-28).

cis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-50)

¹H NMR (400 MHz, chloroform-d) δ ppm 2.23 (br. s., 3H) 2.79-2.86 (m, 2H)2.94 (s, 3H) 3.04 (d, J=4.85 Hz, 3H) 3.27 (q, J=9.70 Hz, 2H) 3.57-3.67(m, 1H) 4.69 (quint., J=8.05 Hz, 1H) 5.20 (br. s., 1H) 6.27 (br. s., 1H)7.94 (br. s., 1H) 8.07 (br. s., 1H); HPLC: RT 1.24 min: MS: m/z: 405.1[M+H]⁺.

cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-28)

¹H NMR (400 MHz, chloroform-d) δ ppm 2.27 (s, 3H) 2.88 (s, 3H) 2.90-3.04(m, 4H) 3.14 (br. s., 3H) 3.61 (quint. J=8.60 Hz, 1H) 4.80 (br. s., 1H)5.32 (br. s., 1H) 7.46 (br. s., 1H) 8.10 (br. s., 1H) 8.23 (s, 1H):HPLC: RT 2.58 min; MS: m/z: 405.1 [M+H]⁺.

Example D-34 and D-35 Synthesis oftrans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-29) andtrans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-30) trans-methyl3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and trans-methyl3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate

To a solution of methyl 3-hydroxycyclobutanecarboxylate (2 g, 15.37mmol), 5-methyl-4-nitro-1H-pyrazole (1.95 g, 15.37 mmol) and PPh: (6.05g, 23.06 mmol) in THF (30 mL) was added dropwise DIAD (4.66 g, 23.06mmol, 4.48 mL) at 0° C. and degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 25° C. for 16 h under N₂. The reactionmixture was concentrated under reduced pressure to remove THF. Theresidue was washed with PE:EtOAc (1:1, 30 mL), filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂. PE:EtOAc=10:1 to 5:1) to give the mixtureof trans-methyl 3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylateand trans-methyl 3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylateas a white solid. LCMS: RT 0.729 min, m/z=240.2 [M+H]⁺.

trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol andtrans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol

To a solution of methyl3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and methyl3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate (1.7 g, 7.11mmol, mixture) in MeOH (20 mL) was added NaBH₄ (672 mg, 17.77 mmol) at0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixturewas quenched by addition of aq. NH₄Cl (20 mL) at 0° C., and extractedwith EtOAc (3×10 mL), washed with brine (5 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, PE:EtOAc=5:1 to 1:1) to givethe mixture oftrans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol andtrans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol as a yellowsolid. LCMS: RT 0.645 min, m/z=212.2 [M+H]⁺.

trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methylmethanesulfonate andtrans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methylmethanesulfonate

To a solution of [3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanoland [3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol (300 mg, 1.42mmol, mixture) in DCM (10 mL) was added MsCl (243 mg, 2.13 mmol, 164.86L) and TEA (287 mg, 2.84 mmol) at 0° C. Then the mixture was stirred at25° C. for 20 min. The reaction mixture was concentrated under reducedpressure to remove CH₃CN (10 mL). The reaction mixture was quenched byaddition water (20 mL) at 0° C., and then extracted with DCM (3×10 mL).The combined organic layers were washed with brine 10 mL, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give themixture of trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methylmethanesulfonate andtrans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methylmethanesulfonate as a yellow oil. LCMS: RT 0.746 min, m/z=290 [M+H]⁺.

trans-2-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile andtrans-2-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile

A mixture of trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methylmethanesulfonate andtrans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methylmethanesulfonate (500 mg, 1.73 mmol), KCN (563 mg, 8.65 mmol) in DMF (10mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 65° C. for 12 h under N₂. The reaction mixture wasquenched by addition H₂O 50 mL at 0° C. and then extracted with EtOAc(3×10 mL). The combined organic layers were washed with brine 10 mL,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the mixture compoundtrans-2-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile andtrans-2-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile as ared oil. LCMS: RT 0.792 min, m/z=221 [M+H]⁺.

trans-2-[3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile andtrans-2-[3-(4-amino-3-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile

A mixture of2-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile, and2-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile (300 mg,1.36 mmol), Fe (379 mg, 6.80 mmol), NH₄Cl (363 mg, 6.80 mmol) in EtOH (4mL) and H₂O (1 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 80° C. for 2 h under N₂ atmosphere. Thereaction mixture was concentrated under reduced pressure to remove EtOH.The residue was diluted with H₂O (20 mL) and extracted with EtOAc (3×10mL). The combined organic layers were washed with aqueous brine 10 mL,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the mixture compoundtrans-2-[3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile andtrans-2-[3-(4-amino-3-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile as ared oil. LCMS: RT 0.099 min, m/z=191 [M+H]⁺.

trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-29) andtrans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-30)

To a solution of2-[3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile, and2-[3-(4-amino-3-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile (100 mg,525.62 μmol) in 1,4-dioxane (3 mL) was added TsOH (45 mg, 262.81 μmol)and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (89 mg,420.50 μmol). The mixture was stirred at 80° C. for 2 h. The reactionmixture was concentrated under reduced pressure, and then purified bytwice of prep-HPLC (FA condition, followed by neutral condition), togive desired compoundtrans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-29) and compoundtrans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-30). LCMS: RT 0.765 min, m/z=366.1 [M+H]⁺.

trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-29)

¹H NMR (400 MHz, CDCl₃) δ ppm 2.18 (s, 3H) 2.42 (ddd, J=12.57, 8.38,3.75 Hz, 2H) 2.62 (d, J=6.62 Hz, 2H) 2.89-3.01 (m, 3H) 3.03 (d, J=4.85Hz, 3H) 4.82-4.94 (m, 1H) 5.15 (br. s., 1H) 8.10 (s, 1H); HPLC: RT 2.71min; MS: m/z: 366.1 [M+H]⁺.

trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile(D-30)

¹H NMR (400 MHz, CDCl₃) δ ppm 2.28 (s, 3H) 2.42 (t, J=8.38 Hz, 2H) 2.60(d, J=5.73 Hz, 2H) 2.79-2.93 (m, 3H) 2.99-3.14 (m, 3H) 4.77-4.90 (m, 1H)5.18 (br. s., 1H) 6.54 (br. s., 1H) 7.88 (br. s., 1H) 8.14 (br. s., 1H);HPLC: RT 1.55 min; MS: m/z: 366.1 [M+H]⁺.

Example D-36 and D-37 Synthesis oftrans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-31) andtrans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-32) trans-methyl3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and trans-methyl3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate

To a solution of methyl 3-hydroxycyclobutanecarboxylate (2 g, 15.37mmol), 5-methyl-4-nitro-1H-pyrazole (1.95 g, 15.37 mmol) and PPh₃ (6.05g, 23.06 mmol) in THF (30 mL) was added dropwise DIAD (4.66 g, 23.06mmol, 4.48 mL) at 0° C. and degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 25° C. for 16 h under N₂. The reactionmixture was concentrated under reduced pressure to remove THF. Theresidue was washed with PE:EtOAc (1:1, 30 mL), filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (SiO₂, PE:EtOAc=10:1 to 5:1) to give the mixture oftrans-methyl 3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate andtrans-methyl 3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate asa white solid. LCMS: RT 0.729 min, m/z=240.2 [M+H]⁺.

trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol andtrans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol

To a solution of trans-methyl3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate, andtrans-methyl 3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate(1.7 g, 7.11 mmol, mixture) in MeOH (20 mL) was added NaBH₄ (672 mg,17.77 mmol) at 0° C. The mixture was stirred at 25° C. for 2 h. Thereaction mixture was quenched by addition of aq. NH₄Cl (20 mL) at 0° C.,and extracted with EtOAc (3×10 mL), washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, PE:EtOAc=5:1 to 1:1) togive the mixture oftrans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol andtrans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol as a yellowsolid. LCMS: RT 0.645 min, m/z=212.2 [M+H]⁺.

trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-4-nitro-pyrazoleandtrans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-4-nitro-pyrazole

A mixture oftrans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol, andtrans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol (500 mg,2.37 mmol, mixture), CuI (90 mg, 474.00 μmol),2,2-difluoro-2-(fluorosulfonyl)acetic acid (633 mg, 3.56 mmol, 368 μL)in CH₃CN (10 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 55° C. for 2 h under N₂. The reaction mixturewas concentrated under reduced pressure to remove CH₃CN (10 mL). Theresidue was purified by prep-TLC (SiO₂. PE:EtOAc=3:1) to give themixture oftrans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-4-nitro-pyrazoleandtrans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-4-nitro-pyrazoleas a colorless oil. LCMS: RT 0.834 min, m/z=262 [M+H]⁺.

trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-amineandtrans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-amine

To a solution of1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-4-nitro-pyrazole, and1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-4-nitro-pyrazole (300mg, 1.15 mmol, mixture) in EtOH (4 mL) and H₂O (1 mL) was added Fe (321mg, 5.75 mmol) and NH₄Cl (307 mg, 5.75 mmol). The mixture was stirred at80° C. for 2 h. The reaction mixture was concentrated under reducedpressure to remove EtOH. The residue was diluted with H₂O (10 mL) andextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine (10 mL, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the mixture compoundtrans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-amineandtrans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-amineas a red oil. LCMS: RT 0.266 min, m/z=232 [M+H]⁺.

trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-31) andtrans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-32)

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (123mg, 583.81 μmol),trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-amine,andtrans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-amine(150 mg, 648.68 μmol, mixture), TsOH (11 mg, 648.68 μmol) in 1,4-dioxane(2 mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 80° C. for 2 h under N₂. The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (FA condition), to give desired compoundtrans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-31) and compoundtrans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-32). LCMS: RT 0.720 min, m/z=407.3 [M+H]⁺.

trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-31)

¹H NMR (400 MHz, CDCl₃) δ ppm 2.19 (s, 3H) 2.32-2.41 (m, 2H) 2.69-2.81(m, 1H) 2.84-2.96 (m, 2H) 3.03 (d, J=4.85 Hz, 3H) 3.95-4.04 (m, 2H) 4.78(quin, J=7.94 Hz, 1H) 5.18 (br. s., 1H) 6.08-6.51 (m, 2H) 8.08 (s, 1H):HPLC: RT 2.07 min; MS: m/z: 407.1 [M+H]⁺.

trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine(D-32)

¹H NMR (400 MHz, CDCl₃) δ ppm 2.29 (s, 3H) 2.40 (t, J=8.82 Hz, 2H)2.62-2.80 (m, 3H) 3.08 (br. s., 3H) 3.97 (d, J=5.73 Hz, 2H) 4.67-4.84(m, 1H) 5.30 (br. s., 1H) 6.06-6.49 (m, 2H) 7.89 (br. s., 1H) 8.09 (br.s., 1H); HPLC: RT 2.06 min; MS: m/z: 407.3.

Example D-38 Synthesis of2-(1-((5-chloro-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile(D-33)

A mixture of2-[1-[(4-amino-5-chloro-pyrazol-1-yl)methyl]cyclopropyl]acetonitrile (70mg, 332.29 μmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine(70 mg, 332.29 μmol) and TFA (76 mg, 664.58 μmol) in dioxane (3 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 100° C. for 2 h under N₂. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with H₂O(20 mL), adjusted pH to 8 by adding aq. NaHCO₃ and then extracted withEtOAc (3×10 mL). The combined organic layers were washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (neutral condition) togive2-(1-((5-chloro-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile(D-33). ¹H NMR (400 MHz. CDCl₃): δ ppm 8.26 (s, 1H), 8.20 (s, 1H), 7.16(br. s., 1H), 5.30 (br. s., 1H), 4.32 (s, 2H), 3.43 (s, 2H), 3.11 (d,J=4.77 Hz, 3H), 0.97-1.02 (m, 2H), 0.78-0.82 (in, 2H): HPLC: RT 2.50min; MS: m/z: 386.0 [M+H]⁺.

Example D-39 Synthesis ofN₁-methyl-N²-(3-methyl-1-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-34)

Compound 39-1 was combined with BnBr and CsCO₃ mn DMF to give compound39-2. Compound 39-2 was combined with 2-chloroacetaldehyde and K₂CO₃ inDMF to give compound 39-3. To compound 39-3 in MeOH was added Pd/C, andthe mixture was stirred under H₂ to produce compound 39-4. Compound 39-4was combined with compound 1-1, PPh₃, and DIAD in THF to give compound39-5. To compound 39-5 in MeOH was added Pd/C, and the mixture wasstirred under H₂ to produce compound 39-6. Compound 39-6, compound 5-5,and TsOH were combined in 1,4-dioxane to give compound D-34. MSm/z=393.1 [M+H]⁺.

Example D-40 Synthesis ofN²-(1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-yl)-3-methyl-1H-pyrazol-4-yl)-N¹-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-36)

Compound 40-1 is first combined with methyl acrylate, and the subsequentproduct is then combined with potassium t-butoxide to give compound40-2. To Compound 40-2 is added HCl to give compound 40-3. Compound 40-3is combined with NaBH₄ in MeOH to produce compound 40-4. Compound 40-4is combined with compound 1-1, PPh₃, and DIAD in THF to give compound40-5. To compound 40-5 in MeOH is added Pd/C, and the mixture is stirredunder H₂ to produce compound 40-6. Compound 40-6, compound 5-5, and TsOHare combined in 1,4-dioxane to give compound D-36.

Compound D-36 can also be synthesized according to the scheme below.

Compound 40-7 was combined with trityl chloride and TEA in DMF to givecompound 40-8. Compound 40-8 was combined with vinylmagnesium bromide inTHF to give compound 40-9. Compound 40-9 was combined with MnO₂ indioxane to give compound 40-10. Compound 40-10 was combined with HBr andacetic acid to give Compound 40-11. Compound 40-11 was combined withCs₂CO₃ in acetonitrile to give compound 40-3. Compound 40-3 was combinedwith NaBH₄ in MeOH to produce compound 40-4. Compound 40-4 was combinedwith compound 1-1, PPh₃, and DIAD in THF to give compound 40-5. Tocompound 40-5 in MeOH was added Pd/C. and the mixture is stirred underH₂ to produce compound 40-6. Compound 40-6, compound 5-5, and TsOH werecombined in 1,4-dioxane to give compound D-36. MS m/z=379.2 [M+H]⁺.

Example D-41 Synthesis ofN²-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N¹-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-38)

Compound 41-1 was combined with trityl chloride and TEA in DMF, andvinylmagnesium bromide was subsequently added to give compound 41-2.Compound 41-2 was combined with MnO₂, and HBr was subsequently added togive compound 41-3. Compound 41-3 was combined with TEA in MeCN, andNaBH₄ was subsequently added to give compound 41-4. Compound 41-4 wascombined with compound 1-1, PPh₃, and DIAD in THF to give compound 41-5.To compound 41-5 in MeOH was added Pd/C, and the mixture was stirredunder H₂ to produce compound 41-6. Compound 41-6, compound 5-5, and TsOHwere combined in 1,4-dioxane to give compound D-38.

Example D-42 Synthesis ofN¹-methyl-N²-(3-methyl-1-(3-methyl-5,6-dihydro-4H-cyclopenta[d]isoxazol-6-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-35)

Compound 42-1 was combined with acetaldehyde oxime, N-chlorosuccinimide,and NaHCO₃ to give compound 42-2. Compound 42-2 was combined with NaBH₄in MeOH to provide compound 42-3. Compound 42-3 was combined withcompound 1-1, PPh₃, and DIAD in THF to give compound 42-4. To compound42-4 in MeOH was added Pd/C, and the mixture was stirred under H₂ toproduce compound 42-5. Compound 42-5, compound 5-5, and TsOH werecombined in 1,4-dioxane to give compound D-35. MS m/z=394.1 [M+H]⁺.

Example D-43 Synthesis ofN¹-methyl-N²-(3-methyl-1-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-37)

Compound 43-1 was combined with methyl hydrazine to give compound 43-2.Compound 43-2 was combined with NaBH₄ in MeOH to give compound 43-3.Compound 43-3 was combined with compound 1-1, PPh₃, and DIAD in THF togive compound 43-4. To compound 43-4 in MeOH was added Pd/C, and themixture was stirred under H₂ to produce compound 43-5. Compound 43-5,compound 5-5, and TsOH were combined in 1,4-dioxane to give compoundD-37. MS m/z=393.1 [M+H]⁺.

Example D-44 Synthesis ofN2-(1-(5,6-dihydro-4H-cyclopenta[d]thiazol-6-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-53),N2-(1-(5,6-dihydro-4H-cyclopenta[d]oxazol-6-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-54),N2-(1-(5,6-dihydro-4H-cyclopenta[d]oxazol-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-51), andN¹-methyl-N²-(3-methyl-1-(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-39)

Compounds D-53, D-43, D-51, and D-39 can be prepared according to thefollowing general scheme, wherein: X is S, Y is CH, and Z is N forcompound D-53; X is O, Y is CH, and Z is N for compound D-54; X is N. Yis CH, Z is O for compound D-51; and X is NH, Y is N, and Z is CH forcompound D-39.

Compound 44-1 is combined with methyl acrylate. Pd(PPh₃)₄, and TEA.Then, to the subsequent product is added Pd/C, and the mixture isstirred under H₂ to produce compound 44-2. Compound 44-2 is combinedwith potassium t-butoxide, followed by HCl, to give compound 44-3.Compound 44-3 is combined with NaBH₄ in MeOH to give compound 44-4.Compound 44-4 is combined with compound 1-1, PPh₃, and DIAD in THF togive compound 44-5. To compound 44-5 in MeOH is added Pd/C, and themixture is stirred under H₂ to produce compound 44-6. Compound 44-6,compound 5-5, and TsOH are combined in 1,4-dioxane to give compound44-7.

Example D-45 Synthesis ofN²-(1-(2-chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-yl)-N₁-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-41)

Compound 45-1 is combined with compound 1-1, PPh₃, and DIAD in THF togive compound 45-2. Compound 45-2 is combined with N-chlorosuccinimideto give compound 45-3. To compound 45-3 in MeOH is added Pd/C, and themixture is stirred under H₂ to produce compound 45-4. Compound 45-4,compound 5-5, and TsOH are combined in 1,4-dioxane to give compoundD-41.

Example D-46 Synthesis ofN2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-55)

Compound 46-1 is combined with TBSCl and imidazole in DMF, and thenEt₃OBF₄ is subsequently added to give compound 46-2. Compound 46-2 iscombined with 2,2-diethoxyethan-1-amine and HCl in EtOH to give compound46-3. Compound 46-3 is combined with HCl in 1,4-dioxane to give compound46-4. Compound 46-4 is combined with compound 1-1, PPh₃, and DIAD in THFto give compound 46-5. To compound 46-5 in MeOH is added Pd/C, and themixture is stirred under H₂ to produce compound 46-6. Compound 46-6,compound 5-5, and TsOH are combined in 1,4-dioxane to give compoundD-55.

Example D-47 Synthesis ofN2-(1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-5-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(D-52)

Compound 30-3 and 3-bromo-2-(bromomethyl)prop-1-ene are combined withK₂CO₃ in DMF to give compound 47-1. Compound 47-1 is combined withlithium bis(trimethylsilyl)amide to give compound 47-2. Compound 47-2 iscombined with NaBH₄ in MeOH to give compound 47-3. Compound 47-3 iscombined with compound 1-1, PPh, and DIAD in THF to give compound 47-4.To compound 47-4 in MeOH is added Pd/C, and the mixture is stirred underH₂ to produce compound 47-5. Compound 47-5, compound 5-5, and TsOH arecombined in 1,4-dioxane to give compound D-52.

Compounds D-17 (MS: (M+H⁺) m/z: 381.1) and D-18 (MS: (M+H⁺) m/z: 381.1)were prepared according to Example D-21 and D-22. Compounds D-40, D-42,and D-43, are prepared according to the Examples above and/or generalprocedures described herein. Compounds D-176 to D-187 are also preparedaccording to the Examples above and/or general procedures describedherein.

Compounds listed in Table D-3 were prepared according to the Examplesabove and/or general procedures described herein. Further, compoundnumbers of Table D-3 correspond to the compound numbers of Table D-1.

TABLE D-3 MS No. [M + H]⁺ D-56 393.1 D-57 410.1 D-58 408.2 D-59 408.1D-60 393.1 D-61 476.2 D-62 413.1 D-63 443.2 D-64 411.2 D-65 393.7 D-66408.1 D-67 379.1 D-68 394.1 D-69 408.2 D-70 381.2 D-71 393.1 D-72 408.2D-73 408.1 D-74 393.1 D-75 444.1 D-76 408.2 D-77 394.2 D-78 407.2 D-79408.1 D-80 395.1 D-81 426.2 D-82 395.1 D-83 411.1 D-84 408.2 D-85 420.1D-86 410.1 D-87 443.2 D-88 425.2 D-89 425.2 D-90 408.2 D-91 408.1 D-92407.2 D-93 407.2 D-94 393.1 D-95 407.2 D-96 381.2 D-97 410.1 D-98 407.1D-99 413.1 D-100 394.1 D-101 380 D-102 393.1 D-103 424.2 D-104 413.1D-105 413.1 D-106 419.2 D-107 408.2 D-108 408.2 D-109 408.1 D-110 393.1D-111 403.1 D-112 408.1 D-113 408.2 D-114 408.2 D-115 394.2 D-116 407.1D-117 408.2 D-118 476.2 D-119 420.1 D-120 381.1 D-121 379.1 D-122 393.1D-123 408.1 D-124 408.2 D-125 408.2 D-126 393.2 D-127 380.1 D-128 404.1D-129 407.1 D-130 379.1 D-131 393.1 D-132 394.2 D-133 408.2 D-134 408.2D-135 476.2 D-136 4082 D-137 379.1 D-138 407.1 D-139 424.2 D-140 420.1D-141 408.1 D-142 380.1 D-143 408.2 D-144 352.2 D-145 393.1 D-146 393.1D-147 419.2 D-148 408.1 D-149 408.2 D-150 379.1 D-151 407.2 D-152 393.2D-153 426.2 D-154 374.2 D-151 366.1 D-156 408.2 D-157 393.1 D-157a 366.1D-158 380.2 D-159 380.1 D-160 394.1 D-161 381 D-162 394.2 D-163 393.1D-164 400 D-165 411.2 D-166 379.1 D-167 411.1 D-168 411.1 D-169 393.1D-170 407.2 D-171 408.2 D-172 393.1 D-173 394.1 D-174 395.1 D-175 408.2D-178 406.1 D-183 377.1 D-184 405.0 D-185 404.1 D-186 361.1 D-187 439.3D-188 393.1 D-189 393.1 D-190 358.1 D-191 358.1 D-192 421.1 D-193 421.2D-194 439.3 D-195 428.3 D-196 428.3 D-197 428.3 D-198 428.3 D-199 376.2D-200 376.1 D-201 384.2 D-202 384.2 D-203 372.2 D-204 390.3 D-205 407.2D-206 407.2

Biological Example Biochemical Assay of the Compounds

Materials: LRRK2 G2019S enzyme, Substrate (LRRKtide), ATP, TR-FRETdilution buffer, pLRRKtide antibody, 384-well assay plate, and DMSO.

Enzyme reaction conditions: 50 mM Tris pH 7.5, 10 mM MgCl₂, 1 mM EGTA,0.01% Brij-35, 2 mM DTT, 5 nM LRRK2, 134 μM ATP, 60 minute reactiontime, 23° C. reaction temperature, and 10 μL total reaction volume.

Detection reaction conditions: 1×TR-FRET dilution buffer, 10 mM EDTA, 2nM antibody, 23° C. reaction temperature, and 10 μL total reactionvolume.

Compound solutions were prepared by initially diluting to 1 mM withDMSO. 35 μL of reference compound solution, 35 μL of test compoundsolution, and 35 μL HPE were successively added to the source plate(384-well assay plate, Labcyte). The plates were centrifuged at 2500 rpmfor 1 minute and sealed in foil. POD was used to perform a 3.162 foldserial dilution and 100 nL of reference compound solution, test compoundsolution, HPE and ZPE were transferred to assay plates. The assay platewas centrifuged at 2500 rpm for 1 minute, and sealed with foil.

To perform the enzyme reaction, 5 μL of LRRKtide substrate and kinasemixture in assay buffer was added to all wells of the assay plate. Theplate was centrifuged to concentrate the mixture at the bottom of thewells. The assay plate was incubated at 23° C. for 20 minutes. Followingincubation, 5 μL of 2×ATP in assay buffer was added to each well, andplates were centrifuged to concentrate the mixture at the bottom of thewells. The plate was incubated at 23° C. for 60 minutes.

To perform the detection of the reaction, EDTA completely mixed inTR-FRET dilution buffer was added to antibody reagent. 10 μL ofdetection reagent was added to all wells of each well of the assay plateand the plate was centrifuged to concentrate the mixture at the bottomof the wells. The plate was then incubated at 23° C. for 60 minutes.Plates were read on Perkin Elmer Envision 2104 instrument in TR-FRETmode using a 340 nm excitation filter, 520 nm fluorescence emissionfilter, and 490 or 495 nm terbium emission filter.

Representative compounds found in Table A-1, B-1, C-1, and D-1 weretested according to the above methods and found to exhibit an LRRK2G2019S IC₅₀ as indicated in Table A-2, B-2, C₂, and D-4 respectively.

TABLE A-2 Activity of Representative Compounds No. IC₅₀ No. IC₅₀ No.IC₅₀ No. IC₅₀ A-1 +++ A-2 +++ A-3 + A-4 ++ A-5 ++ A-7 +++ A-8 +++ A-9 ++A-10 + A-11 ++ A-12 + A-13 + A-14 +++ A-15 +++ A-16 +++ A-17 ++ A-18 ++A-19 ++ A-20 +++ A-21 ++ A-22 + A-23 +++ A-24 +++ A-25 ++ A-26 +++A-27 + A-28 +++ A-29 +++ A-30 +++ A-31 +++ A-32 + A-33 + A-34 +++ A-35+++ A-36 +++ A-37 + A-38 + A-39 +++ A-40 +++ A-41 +++ A-42 + A-43 +++A-44 +++ A-45 +++ A-46 +++ A-47 +++ A-48 +++ A49 + A-50 +++ A-51 +++A-52 + A-53 +++ A-54 +++ A-55 +++ A-56 +++ A-57 + A-58 +++ A-59 +++ A-60+++ A-61 ++ A-62 + A-63 ++ A-64 ++ A-65 +++ A-66 + A-67 +++ A-68 +++A-69 +++ A-70 +++ A-71 +++ A-72 + A-73 +++ A-74 ++ A-75 +++ A-76 + A-77+++ A-78 + A-79 +++ A-80 +++ A-81 +++ A-82 +++ A-83 +++ A-84 +++ A-85+++ A-86 +++ A-87 +++ A-88 + A-89 +++ A-90 +++ A-91 ++ A-92 +++ A-93 +++A-94 +++ A-95 +++ A-96 +++ A-97 ++ +++ = IC₅₀ less than 30 nM; ++ = IC₅₀between 30 nM and 60 nM; + = IC₅₀ greater than 60 nM

TABLE B-2 Activity of Representative Compounds No. IC₅₀ No. IC₅₀ No.IC₅₀ No. IC₅₀ B-1 ++ B-2 +++ B-3 +++ B-4 + B-5 ++ B-6 +++ B-7 + B-8 ++B-9 + B-10 ++ B-11 ++ B-12 + B-13 + B-14 + + = IC₅₀ greater than 2 nm to20 nm; ++ = IC₅₀ greater than 1 nm to 2 nM; +++ = IC₅₀ 1 nM or less

TABLE C-2 Activity and MS data of Representative Compounds No. IC₅₀ [M +H]⁺ C-1 +++ 334.2 C-2 +++ 334.2 C-3 ++ 306.2 C-4 +++ 306.1 C-5 +++ 270.2C-6 +++ 270.1 C-7 +++ 310.2 C-8 +++ 308.2 C-9 +++ 323.2 C-10 +++ 347.2C-11 +++ 358.2 C-12 +++ 358.2 C-13 +++ 337.2 C-14 +++ 340.2 C-15 + 308.1C-16 + 308.2 C-17 + 255.1 C-18 +++ 294.2 C-19 +++ 294.2 C-20 +++ 293.1C-21 +++ 279.1 C-22 +++ 356.1 C-23 +++ 322.2 C-24 +++ 269.1 C-25 +++269.1 C-26 +++ 403.2 C-27 +++ 378.2 C-28 +++ 412.2 C-29 +++ 396.2 C-30+++ 333.2 C-31 +++ 333.2 C-32 +++ 367.1 C-33 + 284.1 C-34 + 284.1 C-35 +269.1 C-36 +++ 310.2 C-37 +++ 378.2 C-38 +++ 330.1 C-39 +++ 330.1 C-40+++ 330.1 C-41 +++ 362.2 C-42 +++ 390.1 C-43 +++ 360.1 C-44 +++ 360.2C-45 +++ 334.1 = [M − H]⁻ C-46 +++ 336.2 C-47 +++ 374.1 C-48 +++ 350.1C-49 +++ 296.1 C-50 +++ 296.1 C-51 +++ 310.1 C-52 +++ 310.1 C-53 +++319.1 C-54 +++ 319.1 C-55 +++ 367.1

TABLE D-4 Activity of Representative Compounds No. IC₅₀ D-1 + D-2 +++D-3 + D-4 +++ D-5 + D-6 +++ D-7 +++ D-8 + D-9 +++ D-10 ++ D-11 +++ D-12+++ D-13 +++ D-14 +++ D-15 +++ D-16 +++ D-17 +++ D-18 + D-19 +++ D-20 +D-21 ++ D-22 +++ D-23 + D-24 +++ D-25 +++ D-26 +++ D-27 +++ D-28 +++D-29 +++ D-30 +++ D-31 +++ D-32 +++ D-33 +++ D-34 +++ D-35 +++ D-36 +D-37 ++ D-44 +++ D-45 +++ D-46 ++ D-47 + D-48 +++ D-49 +++ D-50 +++ D-56+++ D-57 +++ D-58 +++ D-59 +++ D-60 +++ D-61 +++ D-62 + D-63 +++ D-64+++ D-65 +++ D-66 +++ D-67 + D-68 + D-69 +++ D-70 +++ D-71 +++ D-72 +D-73 +++ D-74 +++ D-75 +++ D-76 +++ D-77 +++ D-78 + D-79 +++ D-80 +++D-81 +++ D-82 +++ D-83 +++ D-84 +++ D-85 +++ D-86 +++ D-87 +++ D-88 +++D-89 +++ D-90 +++ D-91 +++ D-92 ++ D-93 +++ D-94 +++ D-95 + D-96 +++D-97 +++ D-98 +++ D-99* +++ D-100 +++ D-101 +++ D-102 +++ D-103 +++D-104 +++ D-105 +++ D-106 +++ D-107 +++ D-108 +++ D-109 +++ D-110 +++D-111 +++ D-112 +++ D-113 +++ D-114 +++ D-115 + D-116 +++ D-117 +++D-118 +++ D-119 +++ D-120 +++ D-121 +++ D-122 +++ D-123 +++ D-124 +++D-125 +++ D-126 + D-127 +++ D-128 +++ D-129 +++ D-130 ++ D-131 +++ D-132+++ D-133 +++ D-134 +++ D-135 +++ D-136 +++ D-137 +++ D-138 +++ D-139+++ D-140 +++ D-141 +++ D-142 + D-143 ++ D-144 +++ D-145 +++ D-146 +++D-147 +++ D-148 +++ D-149 ++ D-150 +++ D-151 +++ D-152 +++ D-153 +++D-154 +++ D-155 +++ D-156 +++ D-157 +++ D-157a +++ D-158 +++ D-159 +++D-160 +++ D-16I +++ D-162 +++ D-163 +++ D-164 +++ D-165 +++ D-166 +++D-167 +++ D-168 +++ D-169 + D-170 +++ D-171 +++ D-172 +++ D-173 + D-174+++ D-175 +++ D-178 +++ D-183 +++ D-184 +++ D-185 +++ D-186 +++ D-187+++ D-188 + D-189 +++ D-190 +++ D-191 +++ D-192 +++ D-193 +++ D-194 +++D-195 +++ D-196 +++ D-197 +++ D-198 +++ D-199 +++ D-200 +++ D-201 +++D-202 +++ D-203 +++ D-204 +++ D-205 + D-206 +++ +++ = IC₅₀ less than 30nM; ++ = IC₅₀ between 30 nM and 60 nM; + = IC₅₀ greater than 60 nM *Datafor D-99 either refers to D-99, D-41, or a mixture of D-41 and D-99.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” “containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed.

Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification, improvement and variation of the inventionsembodied therein herein disclosed may be resorted to by those skilled inthe art, and that such modifications, improvements and variations areconsidered to be within the scope of this invention. The materials,methods, and examples provided here are representative of preferredembodiments, are exemplary, and are not intended as limitations on thescope of the invention.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, to the same extent as if each were incorporated by referenceindividually. In case of conflict, the present specification, includingdefinitions, will control.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

1. A compound having the following formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or a mixture ofstereoisomers, tautomer or prodrug thereof, wherein: Z is N or CH; R¹ ishalo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkyloxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,aminocarbonyl, or heterocyclylcarbonyl, wherein each is optionallysubstituted; and R⁵ is H; or R¹ and R⁵ together with the atom to whichthey are attached form a 5-membered ring having the structure:

Y is N or CR⁶; R⁶ is H, halo, cyano, C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁-C₆ alkoxy, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, —S(O)_(w)(C₁-C₆ alkyl), cycloalkyl, heterocyclyl,heteroaryl, aryl, acyl, or amido, wherein each is optionallysubstituted; R¹⁰ is H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orcycloalkyl; R² is C₁-C₆ alkyl, cycloalkyl, cycloalkylalkyl, C₁-C₆alkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,heterocyclylalkyloxy, amino, C₁-C₆ alkylamino, cycloalkylamino,cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino,wherein each is optionally substituted; R^(3a) and R^(3b) are eachindependently H, halo, cyano, amino, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆heteroalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl,C₁-C₆ alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆alkoxycarbonyl, aminocarbonyl, heterocyclylcarbonyl, or -L²-R⁸, whereineach is optionally substituted; or R⁴ and either R^(3a) or R^(3b) whenattached to an adjacent carbon, together with the atoms bound theretojoin to form a heterocyclyl or heteroaryl, wherein each heterocyclyl orheteroaryl is optionally substituted; or R^(3a) and R^(3b) when attachedto an adjacent carbon, together with the atoms bound thereto join toform a cycloalkyl, heterocyclyl, or heteroaryl, wherein each cycloalkyl,heterocyclyl, or heteroaryl is optionally substituted; R⁴ is H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl,C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ haloalkoxyalkyl, C₁-C₆cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl, heterocyclylcarbonyl, or -L¹-R⁷, wherein each isoptionally substituted; L¹ is —S(O)_(p)—, —S(O)_(p)N(R⁹)—, —(CH₂)_(m)—,—C(O)—, —C(O)O—, or —C(O)N(R⁹)—; each L² is independently —O—,—S(O)_(m)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁹)—,—N(R⁹)C(O)—, —N(R⁹)C(O)—, —OC(O)N(R⁹)—, —N(R⁹)C(O)N(R⁹)—,—S(O)_(p)N(R⁹)—, —N(R⁹)S(O)_(p)N(R⁹)— or —N(R⁹)S(O)_(p)—; R⁷ is C₁-C₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ heteroalkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl, wherein each is optionallysubstituted; each R⁸ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, arylalkyl, heteroaryl, or heteroarylalkyl, wherein each isoptionally substituted; each R⁹ is independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂₋₆ alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; eachp is independently 1 or 2; each w is independently 0, 1 or 2; and each mis independently 0, 1, 2 or 3; provided that: a) when R⁵ is H, then Z isN, and R² is C-heterocyclyl, which is optionally substituted; and b)when R¹ and R⁵ together with the atom to which they are attached formthe 5-membered ring, then either: i) R² is C₁-C₆ alkoxy, cycloalkyloxy,cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino, C₁-C₆alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, orheterocyclylalkylamino; Z is N; R⁵ is H; Y is N or CR⁶; and R⁶ is halo,C₁-C₆ haloalkyl or cycloalkyl; or ii) R² is C₁-C₆ alkyl, cycloalkyl orcycloalkylalkyl, wherein each is optionally substituted.
 2. A compoundof formula (A-Ic):

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer, or prodrug thereof, wherein: R¹¹ is chloro or—CF₃; R¹² is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆alkoxyalkyl, C₁-C₆ haloalkoxyalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl,C₁-C₆ alkylsulfonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl or heterocyclylcarbonyl, wherein each C₁-C₆ alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, or heteroarylalkyl is optionally substituted; and one ofR^(13a) and R^(13b) is H, and the other of R^(13a) and R^(13b) is H,halo, or methyl.
 3. The compound of claim 2, wherein R¹² is C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, cycloalkyl,heterocyclyl, heteroaryl wherein each cycloalkyl, heterocyclyl, orheteroaryl is optionally substituted.
 4. The compound of claim 2 whereinone of R^(13a) or R^(13b) is H, and the other of R^(3a) or R^(3b) ismethyl.
 5. A compound of formula (B-I):

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer or prodrug thereof, wherein: Y is N or CR²¹; R²¹is halo, C₁-C₆ haloalkyl or cycloalkyl; R²² is C₁-C₆ alkoxy;cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,heterocyclylalkyloxy, amino, C₁-C₆ alkylamino, cycloalkylamino,cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino;R^(23a) and R^(23b) are each independently H, halo, cyano, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, C₁-C₆ alkylcarbonyl, C₁-C₆alkoxycarbonyl, aminocarbonyl or heterocyclylcarbonyl; and R²⁴ is H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl,C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, heteroarylylalkyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxycarbonylalkyl,aminocarbonyl or heterocyclylcarbonyl.
 6. The compound of claim 5,wherein Y is N.
 7. The compound of claim 5, wherein Y is CR²¹.
 8. Thecompound of claim 7, wherein R²¹ is chloro.
 9. The compound of claim 7,wherein R²¹ is C₁-C₆ haloalkyl or cycloalkyl.
 10. The compound of claim5, wherein R²² is C₁-C₆ alkoxy or C₁-C₆ alkylamino.
 11. The compound ofclaim 10, wherein R²² is C₁-C₆ alkoxy.
 12. The compound of claim 10,wherein R²² is C₁-C₆ alkylamino.
 13. The compound of any one claim 5,wherein one of R^(23a) or R^(2b) is H, and the other of R^(23a) orR^(23b) is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆hydroxylalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ aminoalkyl, cycloalkyl,cycloalkylalkyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,aminocarbonyl or heterocyclylcarbonyl.
 14. The compound of claim 5,wherein R²⁴ is C₁-C₆ alkyl.
 15. The compound of claim 5, wherein R²⁴ isC₁-C₆ cyanoalkyl.
 16. A compound having the following formula (C-I):

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer or prodrug thereof, wherein: Y is N or CR³⁶; Zis N or CH; R³¹ is C₁-C₆ alkyl, cycloalkyl or cycloalkylalkyl, each ofwhich is optionally substituted; R³² is H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, or -L³-R³⁷, wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted; R³³ and R³⁴ are each independently H, halo, cyano, amino,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L⁴-R³⁸, wherein eachC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted; or or R³³ and R³⁴together with the atom to which they are attached form a cycloalkyl,heterocyclyl or heteroaryl, wherein each cycloalkyl, heterocyclyl andheteroaryl is optionally substituted; or R³² and R³³ together with theatom to which they are attached form a heterocyclyl or heteroaryl,wherein each heterocyclyl and heteroaryl is optionally substituted; R³⁵is H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or cycloalkyl; R³⁶ isH, halo, cyano, C₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, —S(O)_(w)(C₁-C₆alkyl), cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl, or amido,wherein each alkyl, alkoxyl, haloalkyl, alkoxyalkyl, -cycloalkyl,heterocyclyl, heteroaryl, aryl, acyl, or amido are independentlyoptionally substituted; L³ is —S(O)_(p)—, —S(O)_(p)N(R³⁹)—, —(CH₂)_(m)—,—C(O)—, —C(O)O—, or —C(O)N(R³⁹)—; each L⁴ is independently —O—,—S(O)_(w)—, —(CH₂)_(m)—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R³⁹)—,—N(R³⁹)C(O)—, —N(R⁹)C(O)—, —OC(O)N(R³⁹)—, —N(R³⁹)C(O)N(R³⁹)—,—S(O)_(p)N(R³⁹)—, —N(R³⁹)S(O)_(p)N(R³⁹)— or —N(R³⁹)S(O)_(p)—; R³⁷ isC₁-C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl is optionally substituted; each R³⁸ isindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl, wherein each C₁-C₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl isoptionally substituted; each R³⁹ is independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂₋₆ alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; eachp is independently 1 or 2; each w is independently 0, 1 or 2; and each mis independently 0, 1, 2 or
 3. 17. The compound of claim 16, wherein R³¹is cycloalkyl.
 18. The compound of claim 16, wherein R³² is C₁-C₆ alkyl,or cycloalkyl, wherein each C₁-C₆ alkyl and cycloalkyl is optionallysubstituted.
 19. The compound of claim 16, wherein R³² and R³³ are eachindependently C₁-C₆ alkyl.
 20. The compound of claim 16, wherein R³² andR³³ together with the atom to which they are attached form aheterocyclyl or heteroaryl, wherein each heterocyclyl and heteroaryl isoptionally substituted.
 21. The compound of claim 16, wherein R³⁴ is H.22. The compound of claim 16, wherein R³³ and R³⁴ together with the atomto which they are attached form a cycloalkyl, heterocyclyl orheteroaryl, wherein each cycloalkyl, heterocyclyl and heteroaryl isoptionally substituted.
 23. The compound of claim 16, wherein R³⁵ is Hor methyl.
 24. The compound of claim 16, wherein Y is N.
 25. Thecompound of claim 16, wherein Y is CR²⁶.
 26. The compound of claim 25,wherein R³⁶ is C₁-C₆ haloalkyl, cycloalkyl, halo or cyano.
 27. Thecompound of claim 16, wherein Z is N.
 28. The compound of claim 16,wherein Z is CH.
 29. The compound of claim 16, wherein R³⁵ is H; one ofR³³ and R³⁴ is H and the other is halo, cyano, amino, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, or -L⁴-R³⁸, wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted. 30-39. (canceled)
 40. A compound of Table A-1 orTable A-1A or a pharmaceutically acceptable salt, stereoisomer, mixtureof stereoisomers, prodrug, or tautomer thereof.
 41. A compound of TableB-1 or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, prodrug, or tautomer thereof.
 42. A compound selectedfrom Table C-1 or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, prodrug, or tautomer thereof.
 43. (canceled)44. A pharmaceutical composition comprising the compound as in claim 1,or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, prodrug, or tautomer thereof, and a pharmaceuticallyacceptable carrier, diluent or excipient.
 45. A method for treating adisease or condition mediated, at least in part, by LRRK2, the methodcomprising administering an effective amount of the pharmaceuticalcomposition of claim 1 to a subject in need thereof.
 46. The method ofclaim 45, wherein the disease or condition is a neurodegenerativedisease.
 47. The method of claim 46, wherein the neurodegenerativedisease is Parkinson's disease or dementia.
 48. The method of claim 45,wherein the disease or condition is a central nervous system (CNS)disorder.
 49. The method of claim 48, wherein the CNS disorder isAlzheimer's disease or L-Dopa induced dyskinesia.
 50. The method ofclaim 45, wherein the disease or condition is a cancer.
 51. The methodof claim 50, wherein the cancer is kidney cancer, breast cancer,prostate cancer, blood cancer, papillary cancer, lung cancer, acutemyelogenous leukemia or multiple myeloma.
 52. The method of claim 45,wherein the disease or condition is an inflammatory disease.
 53. Themethod of claim 52, wherein the inflammatory disease is leprosy, Crohn'sdisease, inflammatory bowel disease, ulcerative colitis, amyotrophiclateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.
 54. Amethod for enhancing cognitive memory, the method comprisingadministering an effective amount of the pharmaceutical composition ofclaim 44 to a subject in need thereof.
 55. A compound of claim 1 for usein therapy.
 56. A compound of claim 1 for use in the treatment of aneurodegenerative disease, cancer, or an inflammatory disease.
 57. Acompound of claim 1 for use in the treatment of Alzheimer's disease,L-Dopa induced dyskinesia, Parkinson's disease, dementia, ALS, kidneycancer, breast cancer, prostate cancer, blood cancer, papillary cancer,lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy,Crohn's disease, inflammatory bowel disease, ulcerative colitis,amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosingspondylitis.
 58. Use of a compound of claim 1 for the manufacture of amedicament for treating a neurodegenerative disease, cancer, or aninflammatory disease.
 59. Use of a compound of claim 1 for themanufacture of a medicament for treating Alzheimer's disease, L-Dopainduced dyskinesia, Parkinson's disease, dementia, amyotrophic lateralsclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer,papillary cancer, lung cancer, acute myelogenous leukemia, multiplemyeloma, leprosy, Crohn's disease, inflammatory bowel disease,ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis,or ankylosing spondylitis.
 60. A method of preparing a compound offormula (I) of claim 1, comprising coupling a compound of formula (b):

wherein X is halogen, with a compound of formula (c):

under conditions to provide the compound of formula (I).